Functional mesoporous silica nanoparticles for photothermal-controlled drug delivery in vivo

Article abstract of DOI:10.1002/anie.201203993

Release me! A new class of photothermal-responsive [2]rotaxane-appended mesoporous silica nanoparticles (MSNPs) was developed. Remote-controlled movement of the α-cyclodextrin ring (green) upon trans-cis isomerization of the azobenzene axle (red) enables the loading and release of drugs on demand (see scheme). Curcumin-loaded MSNPs were shown to release curcumin into zebrafish larvae upon treatment with visible light or heat. Copyright

Full text of DOI:10.1002/anie.201203993

Angewandte
Chemie
DOI: 10.1002/anie.201203993
Controlled Release
Functional Mesoporous Silica Nanoparticles for Photothermal-Con-
trolled Drug Delivery In Vivo**
Hong Yan, Cathleen Teh, Sivaramapanicker Sreejith, Liangliang Zhu, Anna Kwok, Weiqin Fang,
Xing Ma, Kim Truc Nguyen, Vladimir Korzh, and Yanli Zhao*
Functional mesoporous silica nanoparticles (MSNPs) that can
be readily modulated by controllable triggers, such as
pH value changes,[1] chemical treatments,[2] electrostatic inter-
actions,[3] enzymatic actions,[4] redox changes,[5] and photo-
irradiation,[6] have been used effectivly for controlled drug
delivery. Among these stimulus conditions, photothermal
action can be considered a clean source of energy, and
photothermal-powered molecular machines can be reversibly
operated and do not generate byproducts. Thus, the con-
struction of novel photothermal-powered systems, although
challenging, has been sought after by scientists on account of
their potential applications in the areas of nanostructured
functional materials,[7] molecular switches,[8] molecular logic
gates,[9] and molecular wires.[10]
Photo-switchable azobenzene and its derivatives have
been widely applied in catalysts,[11] sensors,[12] soft materi-
als,[13] and even in biological systems.[14] Current challenges of
using MSNPs as drug carriers for controlled drug delivery
include: how to release drugs without the release of the pore-
blocking units to avoid side effects from the released pore-
blocking units, how to achieve controlled drug release in vivo,
and how to improve the efficiency of drug carriers.[15]
Considering these factors, biocompatible photothermal-
responsive gates linked covalently to the surface of MSNPs
are regarded as one of the best approaches for controlled drug
delivery. Although light-induced switchable rotaxanes based
on the trans–cis photoisomerization of an azobenzene dumb-
bell threaded into the a-cyclodextrin (a-CD) ring have been
well investigated,[16] the synthesis and application of photo-
thermal-responsive rotaxane-mechanized MSNPs for con-
trolled drug delivery have not been reported. In this context,
the development of a simple, efficient, biocompatible, and
remote-controlled MSNP through the use of photothermal-
responsive rotaxanes is of considerable significance.
Herein, we report a novel strategy for the preparation of
photothermal-responsive rotaxane-functionalized MSNPs
and demonstrate this remote-controlled system for in vivo
drug release to wild-type, optically transparent zebrafish
larvae. In particular, the functional nanoparticles can effi-
ciently deliver curcumin to zebrafish larvae for the treatment
of heart failure. The novel MSNPs were functionalized with
[2]rotaxanes in which the a-CD ring is threaded with a linear
photothermal-responsive azobenzene axle containing a pre-
attached stopper at one end (Scheme 1). The stopper unit has
two sulfonic groups, further enhancing the solubility of
individual nanoparticles in aqueous solution. The a-CD ring
in the [2]rotaxane is initially located at the trans-azobenzene
position, which is somewhat removed from the nanoparticle
surface (trans-MSNP-1). It moves to the triazole/ethylene
glycol position upon the trans-to-cis photoisomerization of
[*] Dr. H. Yan, Dr. S. Sreejith, Dr. L. L. Zhu, A. Kwok, W. Fang,
K. T. Nguyen, Prof. Dr. Y. L. Zhao
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, 637371, Singapore (Singapore)
E-mail: zhaoyanli@ntu.edu.sg
Homepage: http://www.ntu.edu.sg/home/zhaoyanli/
X. Ma, Prof. Dr. Y. L. Zhao
School of Materials Science and Engineering
Nanyang Technological University (Singapore)
Dr. C. Teh, Prof. Dr. V. Korzh
Laboratory of Fish Development Biology
Institute of Molecular and Cell Biology (Singapore)
[**] We thank the Singapore National Research Foundation Fellowship
(NRF2009NRF-RF001-015) and Nanyang Technological University
for financial support.
Scheme 1. A graphical representation of the injection of drug-loaded
MSNPs into zebrafish larvae for in vivo drug delivery, triggered by
either heating or visible light irradiation. MSNPs were functionalized
with photothermal-responsive [2]rotaxanes on the surface. The chem-
ical structure of the [2]rotaxane containing the a-CD ring and
azobenzene unit is shown.
Supporting information for this article (experimental details) is
available on the WWW under http://dx.doi.org/10.1002/anie.
201203993.
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the azobenzene unit under irradiation at 365 nm UV light,
physically blocking the pores of the nanoparticles (cis-MSNP-
1). The cis-to-trans isomerization of the azobenzene unit upon
exposure to visible light or heating causes the a-CD ring to
move back to the trans-azobenzene position (trans-MSNP-1).
The back and forth movements of the a-CD ring along the
azobenzene axle result in the closing and opening of nano-
pores, allowing for both drug storage and remote-controlled
release.
A convenient and sequential combination of a template-
directed synthetic pathway[17] and the copper(I)-catalyzed
azide–alkyne cycloaddition (CuAAC) reaction[18] was
adopted for the preparation of photothermal-responsive
[2]rotaxane attached MSNPs (see Supporting Information,
Scheme S3). The azobenzene-containing azide-functionalized
thread (4 in Scheme S1) was stirred with the a-CD ring in
aqueous solution for 2 h, forming the pseudo[2]rotaxane.
MSNPs functionalized with alkynyl side chains were added to
the pseudo[2]rotaxane solution along with CuSO4·5H2O and
sodium ascorbate, and the mixture solution was stirred for
48 h under N2 atmosphere to give the rotaxane functionalized
trans-MSNP-1. The a-CD-based [2]rotaxane (not attached to
a nanoparticle) and the azobenzene axle-functionalized
MSNPs (MSNP-2; without an a-CD ring) were also prepared
as references (Scheme S2,S3). Because the a-CD ring has two
sides and the dumbbell is nonsymmetrical, two stereoisomers
of [2]rotaxane can be formed. For the sake of clarity, we
present only one stereoisomer in which the secondary side of
the a-CD ring faces the naphthalene stopper.
calcd: 1494.4) for pseudo[2]rotaxane and m/z 1714.1
([M+H]+, calcd: 1713.4) for [2]rotaxane (Figure S7).
To determine the association constants (K) the a-CD ring
with the different parts of the thread, we prepared two model
compounds. One with only an azobenzene moity S1 and one
with a triazole moity S5 (Scheme S2,S3). The association
constants of the azobenzene unit S1 with a-CD (determined
by UV spectral titrations) were 4666mÀ1 before irradiation
with 365 nm UV light and 164mÀ1 after irradiation (Fig-
ure S8). Interestingly, the K of the triazole/ethylene glycol
unit S5 and a-CD was 2600mÀ1, which lies between the K
values of the azobenzene unit S1 before and after UV light
irradiation. This result supports the feasibility of a photo-
thermal-controlled back and forth shuttling of the a-CD ring
between the azobenzene and triazole/ethylene glycol units in
the [2]rotaxane. Kinetic studies on thermal cis-to-trans
isomerization of [2]rotaxane at different temperatures indi-
cated that the change in absorbance at 370 nm of the
azobenzene unit (DAabs) after 5 h are 0.067 at 58C, 0.086 at
238C, 0.101 at 288C, and 0.205 at 378C (Figure S9). These
results demonstrate that a) there is good structural stability of
the cis-azobenzene axle in the [2]rotaxane at room temper-
ature for light-controlled drug delivery under the experimen-
tal time frame and b) it would be feasible to apply cis-to-trans
isomerization of the azobenzene axle at human body temper-
ature (378C).
MSNP-1 and reference MSNP-2 were characterized by
TEM, powder XRD, and cross-polarization magic angle
spinning (CP-MAS) solid-state NMR spectroscopy. High-
resolution TEM images of MSNP-1 showed the formation of
uniform spherical mesoporous nanoparticles with an average
diameter of 60 nm (Figure S10). The N2 sorption analysis of
MSNP-1 revealed a type IV BET (Brunauer–Emmett–Teller)
isotherm with a total surface area of 1207 m2 gÀ1. A narrow
BJH (Barrett–Joyner–Halenda) pore-size distribution was
found with an average pore diameter of 3.8 nm. Powder XRD
further confirmed the well-ordered structures of the func-
tional MSNPs.
Detailed investigations to characterize the structures of
the pseudo[2]rotaxane (Figure S2) and [2]rotaxane (Fig-
ure S3) and to show the photothermal-induced movement
of the a-CD ring between the azobenzene moiety and the
triazole/ethylene glycol unit in [2]rotaxane were carried out
1
1
by H NMR spectroscopy, H ROESY NMR, UV/Vis spec-
troscopy, CD, and ESI-MS techniques. For the 1H NMR
spectroscopy, pseudo[2]rotaxane was prepared by vigorously
stirring thread 4 and the a-CD ring in a 1:2 ratio in D2O
(Figure S2). Downfield shifts of protons Ha–g on the azoben-
zene unit in the presence of the a-CD ring clearly indicated
that the trans-azobenzene moiety of 4 is within the a-CD
cavity, forming pseudo[2]rotaxane.[9,19] Irradiation with
365 nm UV light for 30 minuntes formed the cis and trans
isomers in a 2:1 ratio. Similarly, the trans-to-cis isomerization
of the azobenzene unit in [2]rotaxane resulted in shifts of the
protons Ha–g upon the UV irradiation, and the proton shifts
could be recovered with visible light irradiation or heating
(Figure S3). The 1H ROESY spectrum of [2]rotaxane showed
that the aromatic protons Hf and Hg of the azobenzene unit
are spatially close to the internal protons H5 and H3 of the a-
CD ring (Figure S4).
13C CP-MAS solid-state NMR spectroscopy provides solid
evidence for the formation of the [2]rotaxane-functionalized
silica nanoparticles (Figure S11). A comparison of the solid-
state NMR spectra of MSNP-1 and MSNP-2 was carried out.
The signals at 10.1, 26.6, 36.7, 42.7, and 48.4 ppm are assigned
to aliphatic carbon atoms of the dumbbell component in
MSNP-1, and signals at 115.2, 125.2, 129.7, 141.8, 151.7, and
156.8 ppm are attributed to the aromatic carbon atoms of
the azobenzene unit in MSNP-1. The signal at 169.7 ppm
is characteristic of the carbon atom from a carboxy group
=
(C O). The grafting of the [2]rotaxanes on the MSNPs was
confirmed by a substantial broadening of carbon resonances
around 10–70 ppm, which was the result of the carbon atom
signals from the a-CD ring.
Figure 1 shows the change in the UV/Vis spectra of
photothermal-responsive MSNP-1 in aqueous solution. The
nanoparticle solution was stirred during UV and visible light
irradiation and heating (658C) to avoid precipitation of
MSNPs. A temperature of 658C was used to accelerate the
cis-to-trans isomerization of the azobenzene unit in this study.
In general, the spectral evolution for the trans–cis isomer-
The UVabsorption changes at 370 nm (Figure S5) and CD
spectral changes at 360 nm (Figure S6) for the azobenzene
unit of the [2]rotaxane upon alternating irradiation with UV
and visible light or heating revealed that the switching process
of the a-CD ring is reversible and controllable. The formation
of pseudo[2]rotaxane and [2]rotaxane was also studied by
ESI-MS, giving molecular weights of m/z 1495.6 ([M+H]+,
2
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(0.001 mmol) leached into the aqueous solution, indicating
that MSNP-1 is suitable for drug storage. Next, the release of
RhB from MSNP-1 under visible light irradiation was
monitored by UV/Vis spectroscopy at 58C. The cis-to-trans
photoisomerization of the azobenzene unit under visible light
irradiation enabled the a-CD ring to move back to the trans-
azobenzene position, which led to the opening of the nano-
pores for drug release.
We then carried out control experiments with nonfunc-
tionalized silica nanoparticles 8 and a-CD-less MSNP-2, to
confirm that cargo release depends on the presence of the a-
CD ring on MSNPs. First, nanoparticle 8 was loaded with
RhB and then washed using the same procedure as above. No
obvious changes in both the absorption and emission spectra
of 8 upon visible light irradiation were detected, indicating
a lack of dye loading into the nanoparticles. Next, the role of
the trans–cis photoisomerisation of the azobenzene unit
without the a-CD ring on the surface of MSNPs was
investigated using MSNP-2. After MSNP-2 was loaded with
RhB and washed, the absorption intensities were measured
both in the dark and after visible light irradiation. In the dark,
a gradual absorption enhancement from released RhB
(within ten minutes) was observed. As expected, a rapid
and uncontrolled release of RhB from MSNP-2 was seen
upon the irradiation with visible light (Figure S14). The
significant amount of cargo leakage from RhB-loaded MSNP-
2, even in the dark, confirms that the azobenzene unit in the
absence of an a-CD ring cannot efficiently block the nano-
pores.
Figure 1. Changes in the UV/Vis absorption spectra of MSNP-
1 (1.67 mgmLÀ1) in aqueous solution after irradiation for 20 minutes
with 365 nm UV light (blue) and then after either 15 minutes of visible
light irradiation or 30 minutes of heating at 658C (red). Inset: the
change in absorbance at 370 nm of MSNP-1 as a function of cycles
upon either alternating UV and visible light irradiation (top) or
alternating UV light irradiation and heating at 658C (bottom).
ization of the azobenzene unit had different features (i.e.
a decrease of the absorption band at 370 nm by UV light
irradiation and an increase of this band by either visible light
irradiation or heating to 658C), showing the back and forth
movements of the a-CD ring along the azobenzene axle on
the surface of MSNPs. The azobenzene unit reached its
photostationary state within 10 minutes under the UV light
irradiation, 15 minutes under visible light irradiation, and
30 minutes with heating (658C). The inset plots of Figure 1,
show the UV absorbance changes at 370 nm as a function of
cycles under either alternating UVand visible light irradiation
or alternating UV light irradiation and heating at 658C. This
result reveals that the photothermal-switching process of the
[2]rotaxane on MSNPs is reversible. MSNP-2 also showed
a similar trans–cis isomerization process upon UV and visible
light irradiation (Figure S12).
With the design of nanoparticle carriers for in vivo
photothermal therapy in mind, the drug-release properties
of curcumin-loaded MSNP-1, triggered by visible light or
heating, were investigated in solution (Figure 2, Fig-
ures S15,S16). The difference in drug release between visible
light irradiation and heating was monitored by the time-
dependent release from the curcumin-loaded MSNP-1 in
To investigate the photothermal-induced drug release of
MSNP-1, rhodamine B (RhB) and curcumin were employed
as cargos. Fluorescent RhB can be considered as a charged
drug molecule. Curcumin, the dietary polyphenol derived
from turmeric (Curcuma longa), has been shown to be
a potential therapeutic agent, including as an antitumor,
antioxidant, and anti-inflammatory drug.[20] The preparation
of either curcumin- or RhB-loaded MSNP-1 is explained in
the Supporting Information. When the a-CD ring is located
on the trans-azobenzene unit of MSNP-1, it does not block the
nanopore and thus the drugs can be loaded into the nano-
pores. Upon irradiation with 365 nm UV light on the drug-
loaded MSNP-1, the trans-to-cis photoisomerization of the
azobenzene unit enabled the a-CD ring to shift from the
azobenzene unit to the triazole/ethylene glycol position and
trapped the drugs within the nanopores. To examine the
capping efficiency of the a-CD ring, the release profile of
RhB-loaded trans-MSNP-1 was recorded in the dark for 24 h.
As shown in Figure S13, a negligible amount of RhB
Figure 2. Release experiments of curcumin-loaded MSNP-
1 (1.0 mgmLÀ1) were carried out in H2O/EtOH (v/v 4:1), the excitation
wavelength (lex) is 420 nm, and emission was recorded at 537 nm.
Curves (A) and (C) are continuously recorded fluorescence intensity in
the dark at 58C and 378C, respectively, and curve (B) shows the
fluorescence intensity every 5 min with visible light irradiation at 58C.
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solution (H2O/EtOH v/v 4:1). In general, the treatment with
either visible light or heating on the solution produces distinct
release profiles. In Figure 2, the triggered release of fluores-
cent curcumin by visible light irradiation (B) and heating to
378C (C) of the solution of curcumin-loaded MSNP-1 are
shown as gradual enhancements of the emission intensities.
The curcumin release upon heating appears to be more
significant than that from visible light irradiation. Thus, the
high releasing efficiency of MSNP-1 controlled by the cis-to-
trans isomerization of the rotaxane unit upon heating makes
the nanoparticles an excellent model for thermal-triggered
therapy in vivo.
The drug-release efficacy of MSNP-1 was then evaluated
in vivo using optically transparent zebrafish larvae. A sus-
pension of curcumin-loaded MSNP-1 (0.1 mgmLÀ1) was
injected into the brain ventricle of five-day-old zebrafish
larvae. Curcumin is naturally fluorescent in the visible green
spectrum. For photo-induced drug release, we compared the
fluorescence intensities between the larvae incubated in the
dark at 248C (Figure 3C) and the ones that underwent
continuous illumination with visible light for a period of one
hour at 248C (Figure 3D). For thermal-responsive drug
release, we compared the fluorescence intensities between
the larvae incubated in the dark at 248C (Figure 3E) and the
ones incubated in the dark at 378C for a period of one hour
(Figure 3F). The boxed region delimits the zebrafish brain
exposed to the curcumin-loaded MSNP-1 and the fluores-
cence intensity was measured over the boxed area. Curcumin-
loaded MSNP-1 showed good drug release when treated with
either visible light or heated, both in solution and in vivo
(Figure 2, Figure 3, and Figure S16). When compared to the
11.5% reduction in mean fluorescence intensity (Fig-
ure 3A,B) in injected larvae that were incubated in the
dark, 34.9% and 45.9% reductions in mean fluorescence
intensity were observed in vivo after visible light irradiation
at 248C for one hour and treatment at 378C for one hour,
respectively. Decreases in the fluorescence intensity of
curcumin can be explained by in vivo metabolism of the
released curcumin. Importantly, our in vivo results are con-
sistent with the drug release of MSNP-1 in solution, wherein
thermally-triggered drug release was more efficient than
photo-triggered release. Mean fluorescence intensity changes
were calculated from four independent in vivo drug-release
experiments using different amounts of curcumin-loaded
MSNP-1 (Figure S17).
One leading mechanism for heart failure is oxidative
stress. Curcumin has been found to be an effective therapy of
such heart failure, since curcumin is an excellent antioxi-
dant.[20] However, one current issue for curcumin-based
therapeutics is their low solubility in aqueous solutions. To
investigate the therapeutic potential of curcumin-loaded
MSNP-1 on
a
zebrafish-based heart-failure model,
Figure 3. Fluorescence intensities of zebrafish brains microinjected
with curcumin-loaded MSNP-1. Fluorescent images were acquired
immediately after injection (A) and after 1 h in the dark at 248C (B);
immediately after injection in the dark (C) and after 1 h with continu-
ous visible light illumination at 248C (D), and immediately after
injection in the dark at 248C (E) and after 1 h in the dark at 378C (F).
Initial mean fluorescence intensity (A,C,E) was normalized to 100%
and the intensity after 1 h (B,D,F) was calculated as a percentage of
the initial signal (using Image J software).
0.1 mgmLÀ1 of either curcumin suspension or curcumin-
loaded MSNP-1 was injected into the venous sinus of
zebrafish larvae experiencing heart failure. Ventricle con-
tractility and heartbeat were assessed after incubating the
larvae at 378C for one hour. Manipulated larvae and wild-
type controls were subsequently incubated at 28.58C. Figure 4
shows the effect of curcumin toward improving cardiac output
Figure 4. Therapeutic results of curcumin on improving cardiac output of SqKR15 zebrafish larvae experiencing heart failure. Heartbeat of
zebrafish experiencing heart failure (A), after microinjection of curcumin into the heart (B), and after microinjection of curcumin-loaded MSNP-
1 into the heart (C). Larvae were incubated at 378C for 1 h before measuring the ventricle contractility and heartbeat. FS=fractional shortening;
bpm=beats per minute.
4
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[4] a) K. Patel, S. Angelos, W. R. Dichtel, A. Coskun, Y. W. Yang,
of SqKR15 zebrafish larvae experiencing heart failure. When
compared to untreated larvae experiencing heart failure
(Figure 4A) and larvae treated with curcumin alone (Fig-
ure 4B), there was a significant improvement in heartbeats
per minute (bpm) and contractility (expressed by fractional
shortening (FS) that is defined in Figure S18) after treatment
with curcumin-loaded MSNP-1 (Figure 4C). The treatment of
heart failure by thermal-triggered curcumin-loaded MSNP-
1 leads to an FS of 0.27 and 70 bpm, close to the values of
normal zebrafish larvae. The heart rate of normal zebrafish
larvae ranges from 80 to 160 bpm.[21] This result strongly
demonstrates that the curcumin-loaded MSNP-1 can serve as
an efficient technique for in vivo drug delivery.
In conclusion, we have developed a novel strategy for the
preparation of a new class of photothermal-responsive
rotaxane-functionalized mesoporous silica nanoparticles
(MSNP-1). The remote-controlled drug release is based on
the back and forth movement of the a-CD ring owing to
photothermal-induced reversible trans–cis isomerization of
the azobenzene axle. MSNP-1 has been successfully used for
in vivo release of curcumin into five-day-old zebrafish
embryos. Efficient thermal-triggered release of curcumin
from drug-loaded MSNP-1 was shown to be effective against
heart failure in zebrafish larvae and has shed light on future
applications of functional nanoparticles. The controllable
character of the MSNP-1 system, easily powered by light and
temperature, makes it an excellent drug carrier for therapeu-
tic applications. Investigations are ongoing, and we will
employ this integrated system to perform targeted photo-
thermal-induced drug release both in vitro and in vivo.
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Received: May 23, 2012
Published online: && &&, &&&&
Keywords: drug delivery · mesoporous silica nanoparticles ·
.
nanoparticles · photothermal switches · zebrafish
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
Angewandte
Communications
Communications
Controlled Release
Release me! A new class of photothermal-
responsive [2]rotaxane-appended meso-
porous silica nanoparticles (MSNPs) was
developed. Remote-controlled movement
of the a-cyclodextrin ring (green) upon
trans–cis isomerization of the azobenzene
axle (red) enables the loading and release
of drugs on demand (see scheme).
H. Yan, C. Teh, S. Sreejith, L. L. Zhu,
A. Kwok, W. Fang, X. Ma, K. T. Nguyen,
V. Korzh, Y. L. Zhao*
&&&& — &&&&
Functional Mesoporous Silica
Nanoparticles for Photothermal-
Controlled Drug Delivery In Vivo
Curcumin-loaded MSNPs were shown to
release curcumin into zebrafish larvae
upon treatment with visible light or heat.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!