A new and facile method to prepare uniform hollow MnO/functionalized mSiO₂ core/shell nanocomposites.
ABSTRACT Trifunctional uniform nanoparticles comprising a manganese nanocrystal core and a functionalized mesoporous silica shell (MnO@mSiO(2)(Ir)@PEG, where Ir is an emissive iridium complex and PEG is polyethylene glycol) have been strategically designed and synthesized. The T(1) signal can be optimized by forming hollow core (H-MnO@mSiO(2)(Ir)@PEG) via a novel and facile etching process, for which the mechanism has been discussed in detail. Systematic investigation on correlation for longitudinal relaxation (T(1)) versus core shapes and shell silica porosity of the nanocomposites (MnO, H-MnO, MnO@SiO(2), MnO@mSiO(2), H-MnO@mSiO(2)) has been carried out. The results show that the worm-like nanochannels in the mesoporous silica shell not only increase water permeability to the interior hollow manganese oxide core for T(1) signal but also enhance photodynamic therapy (PDT) efficacy by enabling the free diffusion of oxygen. Notably, the H-MnO@mSiO(2)(Ir)@PEG nanocomposite with promising r(1) relaxivity demonstrates its versatility, in which the magnetic core provides the capability for magnetic resonance imaging, while the simultaneous red phosphorescence and singlet oxygen generation from the Ir complex are capable of providing optical imaging and inducing apoptosis, respectively.
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ABSTRACT: The preparation of thermoresponsive drug carriers with a self-destruction property is presented. These drug carriers were fabricated by incorporation of drug molecules and thermoresponsive copolymer, poly(N-isopropylacrylamide-co-acrylamide), into silica nanoparticles in a one-pot preparation process. The enhanced drug release was primarily attributed to faster molecule diffusion resulting from the particle decomposition triggered by phase transformation of the copolymer upon the temperature change. The decomposition of the drug carriers into small fragments should benefit their fast excretion from the body. In addition, the resulting drug-loaded nanoparticles showed faster drug release in an acidic environment (pH 5) than in a neutral one. The controlled drug release of methylene blue and doxorubicin hydrochloride and the self-decomposition of the drug carriers were successfully characterized by using TEM, UV/Vis spectroscopy, and confocal microscopy. Together with the nontoxicity and excellent biocompatibility of the copolymer/SiO2 composite, the features of controlled drug release and simultaneous carrier self-destruction provided a promising opportunity for designing various novel drug-delivery systems.Chemistry - A European Journal 08/2014; · 5.93 Impact Factor
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ABSTRACT: The room-temperature, aqueous-phase synthesis of iron-oxide nanoparticles (IO NPs) with glutathione (GSH) is reported. The simple, one-step reduction involves GSH as a capping agent and tetrakis(hydroxymethyl)phosphonium chloride (THPC) as the reducing agent; GSH is an anti-oxidant that is abundant in the human body while THPC is commonly used in the synthesis of noble-metal clusters. Due to their low magnetization and good water-dispersibility, the resulting GSH-IO NPs, which are 3.72 ± 0.12 nm in diameter, exhibit a low r2 relaxivity (8.28 mm−1s−1) and r2/r1 ratio (2.28)—both of which are critical for T1 contrast agents. This, together with the excellent biocompatibility, makes these NPs an ideal candidate to be a T1 contrast agent. Its capability in cellular imaging is illustrated by the high signal intensity in the T1-weighted magnetic resonance imaging (MRI) of treated HeLa cells. Surprisingly, the GSH-IO NPs escape ingestion by the hepatic reticuloendothelial system, enabling strong vascular enhancement at the internal carotid artery and superior sagittal sinus, where detection of the thrombus is critical for diagnosing a stroke. Moreover, serial T1- and T2-weighted time-dependent MR images are resolved for a rat's kidneys, unveiling detailed cortical-medullary anatomy and renal physiological functions. The newly developed GSH-IO NPs thus open a new dimension in efforts towards high-performance, long-circulating MRI contrast agents that have biotargeting potential.Small 07/2014; · 7.82 Impact Factor
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ABSTRACT: Molecular imaging non-invasively visualizes and characterizes the biologic functions and mechanisms in living organisms at a molecular level. In recent years, advances in imaging instruments, imaging probes, assay methods, and quantification techniques has enabled more refined and reliable images for more accurate diagnoses. Multimodal imaging combines two or more imaging modalities into one system to produce details in clinical diagnostic imaging that are more precise than conventional imaging. Multimodal imaging offers complementary advantages: high spatial resolution, soft tissue contrast, and biological information on the molecular level with high sensitivity. However, combining all modalities into a single imaging probe involves problems yet to be solved due to the requirement of high dose contrast agents for a component of imaging modality with low sensitivity. The introduction of targeting moieties into the probes enhances the specific binding of targeted multimodal imaging modalities and selective accumulation of the imaging agents at a disease site to provide more accurate diagnoses. An extensive list of prior reports on the targeted multimodal imaging probes categorized by each modality is presented and discussed. In addition to accurate diagnosis, targeted multimodal imaging agents carrying therapeutic medications make it possible to visualize the theranostic effect and the progress of disease. This will facilitate the development of an imaging-guided therapy, which will widen the application of the targeted multimodal imaging field to experiments in vivo.Advanced Drug Delivery Reviews. 01/2014;
PENG ET AL.
’ NO. 5
May 06, 2011
C2011 American Chemical Society
A New and Facile Method To Prepare
Uniform Hollow MnO/Functionalized
Yung-Kang Peng,†Chih-Wei Lai,†Chien-Liang Liu,†Hsieh-Chih Chen,†Yi-Hsuan Hsiao,†Wei-Liang Liu,‡
Kuo-Chun Tang,†Yun Chi,‡Jong-Kai Hsiao,§,^,*Kun-Eng Lim,§,^Hung-En Liao,§Jing-Jong Shyue,)
†Department of Chemistry, National Taiwan University, Taipei 106, Taiwan,‡Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan,
§Department of Medical Imaging, Buddhist Tzu Chi General Hospital, Taipei Branch, Taiwan,^School of Medicine, Tzu Chi University, Hualien, Taiwan, and
Research Center for Applied Science, Academia Sinica, Taipei 115, Taiwan
que for the clinical diagnosis owing to a
number of advantages such as unlimited
tissue penetration, zero ionizing radiation,
nanocolloids possess higher water proton
metal ions in nanoparticles are densely
populated. Contrast agents, such as super-
paramagnetic iron oxides (SPIOs) and ultra-
used in tumor targeting and imaging.4?8
Since T2-weighted imaging usually produces
which is subject to less artifacts and higher
signal intensity of the target organs and
tissues, provides advantageous alterna-
tives. In light of this development, the
have recently proven to be interesting
candidates as contrast agents by shorten-
ing the longitudinal (or spin?lattice) relax-
ation time T1.9
However, a major requirement for a suc-
cessful application of magnetic NPs in bio-
to possess good colloidal stability and low
toxicity in a biological environment. To en-
dow these hydrophobic MnO NPs with hy-
drophilic and biocompatible properties,
various surface modification methods are
adopted. The PEG (polyethylene glycol)-
phospholipid block copolymers could form
tion between hydrophobic tail groups of
specific targeting is another consideration
around the NPs. As for shell coating, silica
agnetic resonance imaging (MRI)
has received much attention over
the past two decades as a techni-
for MnO NPs, which can be prepared by
conjugating PEG-phospholipid with Her-2/
neu receptor antibody.9Schladt et al. fabri-
cated multifunctional MnO NPs functiona-
lized with a dopamine-PEG-protoporphyrin
IX (DA-PEG-PP) ligand for simultaneous op-
tical and MRI imaging andcancer treatment
using photodynamic therapy (PDT).11
The above-mentioned approaches re-
quire sophisticated and elaborate ligand
design to anchor MnO NPs for specific
targeting, optical imaging, biocompatible
and drug delivery properties. Syntheses of
these multifunctionalized ligands, however,
be applicable for large-scale production.
Another strategy for surface modification
is the formation of biocompatible shells
*Address correspondence to
Received for review March 10, 2011
and accepted April 25, 2011.
and PEG is polyethylene glycol) have been strategically designed and synthesized. The T1signal can
for which the mechanism has been discussed in detail. Systematic investigation on correlation for
longitudinal relaxation (T1)versus core shapes andshell silica porosityof thenanocomposites (MnO,
H-MnO, MnO@SiO2, MnO@mSiO2, H-MnO@mSiO2) has been carried out. The results show that the
worm-like nanochannels in the mesoporous silica shell not only increase water permeability to the
interior hollow manganese oxide core for T1signal but also enhance photodynamic therapy (PDT)
efficacy by enabling the free diffusion of oxygen. Notably, the H-MnO@mSiO2(Ir)@PEG nanocompo-
oxygen generation from the Ir complex are capable of providing optical imaging and inducing
KEYWORDS: T1contrast agent.MnO.hollow MnO.mesoporous silica.
dual imaging.photodynamic therapy
PENG ET AL.
’ NO. 5
has been widely applied to protect the NPs from the
external environment and thereby improve the stabi-
much easier to incorporate dyes and photosensitizers
into the silica framework and modify amines, carboxyl
groups, antibodies, and PEG, etc., onto the silica outer-
most surface by end-labeled silane derivatives via
the facile sol?gel chemistry. Unfortunately, with the
nonporous silica shell coating, the manganese oxide
core might not be easily accessible with water mol-
ecules. This is mainly due to the fact that nonporous
silica slows down the exchange rate of water
Recently, hollow MnO NPs became a focusing issue.
Hyeon and co-workers have synthesized hollow MnO
nanoparticles with acid etching under high tempera-
ture (300 ?C) using the impurity alkylphosphonic acid
intechnical gradeof TOPOas the etchant attributed to
Kirkendall effect.14This effect comes from the outward
diffusion of the constituting materials, and the simul-
taneous inward diffusion of vacancies results in the
formation of a void in the core. The hollow Mn3O4
nanoparticles were then synthesized by oxidation of
the surface of MnO nanoparticles under prolonged
reaction time (this takes several days), followed by
selective removal of the core of nanoparticles in an
acidic buffer.10Notably, hollow structured MnO NPs
showed superior spin relaxation enhancement effect
due to the increased concentration of MR-active
Mn2þions exposed at the hollow inner surface for
contacting with water.10,14Moreover, hollow MnO
nanoparticles have been reported to enhance the
spin relaxation up to 6-fold and possess a unique
property of a nanocavity suited for potential drug
delivery in vivo.10
Herein, we employ a new and facile method to
prepare hollow manganese oxide nanoparticles using
simple chemicals, ethylacetate and sodium hydroxide,
under relatively much lower temperature (60 ?C) and
the carboxylate anion potentially acts as a ligand to
extrude the core MnO via Kirkendall effect (vide infra),
ing process is very mild, as demonstrated by co-con-
densation of an Ir(III) complex phosphorescence dye
into H-MnO(core)/SiO2(shell), which retains its intense
phosphorescence after etching, forming H-MnO/SiO2-
(Ir) core/shell nanoparticles (Ir: an Ir(III) complex). We
then moved one more step to prepare a novel core?
shell nanostructure (H-MnO@mSiO2), in which the
hollow core is buried in the mesoporous silica
(mSiO2) shell. Despite the well-established synthetic
protocols on nanostructural magnetic nanoparticle
Mn(þ2)O nanoparticles with mesoporous silica shell
and its bioapplication.
Also, in this study, a series of nanostructures, includ-
ing MnO, H-MnO, MnO@SiO2, MnO@mSiO2, and
H-MnO@mSiO2, were prepared, in which the core
MnO could be in a solid sphere or hollow shape, while
shell SiO2could be nonporous or mesoporous, so that
systematic investigation of correlation on longitudinal
relaxation (T1) versus core shapes and shell silica por-
the H-MnO@mSiO2(Ir)@PEG nanocomposite with pro-
mising r1relaxivity is then used to demonstrate its
versatility in magnetic resonance imaging, phosphor-
escence imaging, and singlet oxygen production, that
are elaborated upon in the following sections.
RESULTS AND DISCUSSION
Synthesis and Characterization. Using the final-stage
nanocomposite H-MnO@mSiO2(Ir)@PEG as the proto-
type, Scheme 1 illustrates the overall synthetic proto-
col. First of all, manganese oxide nanocrystals are
synthesized by using a facile thermal decomposition
method.21These nanocrystals are typically stabilized
to the aqueous phase by utilizing cetyltrimethylam-
monium bromide (CTAB). In the subsequent sol?gel
reaction, CTAB-stabilized nanocrystals act as seeds for
the formation of spherical mesoporous silica shells by
hydrolysis and condensation of tetraethylorthosilicate
(TEOS). Herein, CTAB serves as not only the stabilizing
secondary surfactant for the transfer of the nanocryst-
als to the aqueous phase but also the organic tem-
The structure of the as-synthesized iridium complex
isoquinolinate]2iridium) (Ir(III) complex) (Figure 1A) is
advanced by intentionally direct connecting the
(EtO)3Si functional group, so that it is simultaneously
encapsulated into the mesoporous silica frame-
work during the co-condensation reaction. This
new strategic design can avoid any possible leakage
of the iridium complex, such as [Ir(piq)2(ppTES)] (see
Figure 1B), used in our previous report,22due to the
relative weak ligation between the sensitizer part
and the silanol group.
In this core/shell structure, the silica?CTAB layer is
formed around the CTAB?MnO nanoparticles under
basic conditions through an electrostatic interaction
between the cationic (CTAB) and anionic (silicate)
species.23To further fabricate hollow MnO within a
core?shell nanocomposite, EA/NaOH(aq) (3 mL of EA
and 50 mL of H2O (4 mg of NaOH)) solution is then
introduced. ThehollowMnOcore ofH-MnO@mSiO2(Ir)
could be obtained by applying the etching process to
the as-synthesized nanocomposite, MnO@mSiO2(Ir).
Details of the associated mechanism will be discussed
in the following section. H-MnO@mSiO2(Ir) was then
PENG ET AL.
’ NO. 5
modified by silane-functionalized PEG on the outmost
surfaces. The CTAB templates were then removed via
an ion exchange method,24leaving the void of nano-
channels, which not only enhances PDT efficiency by
water permeability to the interior hollow manganese
oxide core for T1signal. Note that the reverse process,
that is, removing CTAB, followed by modification with
PEG, causes the obstruction of the nanochannels due
to the penetration of PEG (vide infra).
Physical and Photophysical Properties. Figure 2A shows
the transmission electron microscopy (TEM) image of
the oleic-acid-capped MnO nanocrystals, which are
synthesized by thermal decomposition of Mn-oleate
capped MnO NPs are homogeneous and well-dis-
persed. The average diameter is about 23.4 ( 0.7 nm
according to the TEM image. Prior to coating the
mesoporous silica shell onto the MnO nanoparticles,
the oleic-acid-capped MnO NPs have been surface
unchanged in aqueous solution (Figure S1A in Sup-
porting Information). After coating the silica shell,
modifying PEG on outmost surface, followed by CTAB
extraction via ion exchange, Figure 2B shows the
image of the MnO@mSiO2(Ir)@PEG nanocomposite,
in which the mesoporous silica shell clearly possesses
a worm-like channel. The average size of the as-pre-
pared nanocomposites is measured to be 80 ( 2.5 nm
in diameter. After treatment of MnO@mSiO2(Ir)@PEG
with EA/NaOH, the TEM image of the resulting
SiO2, in which each H-MnO core is encapsulated by a
Scheme 1. Schematic illustration of the synthetic procedure for H-MnO@mSiO2(Ir)@PEG nanocomposites.
Figure 1. (A) Ir(III) complex used in this study, compared with (B) [Ir(piq)2(ppTES)] used in ref 25.
PENG ET AL.
’ NO. 5
∼30 nm thick silica layer. The size of H-MnO@mSiO2-
(Ir)@PEG is very uniform, as evidenced by the unifor-
mity (σ< 3.5%) (statistic in Figure S1B in Supporting
Information) of the as-prepared nanocomposites cov-
ering a large area (3.5 ? 3.5 μm2) in the TEM image
(Figure 2D). The diameter could be easily controlled by
varying the concentration of the core nanocrystals
during the formation of the mesoporous silica shell
(Figure S2). The N2adsorption?desorption isotherms
(see Figure S3) exhibit a characteristic type IV isotherm
according to the IUPAC classification,25demonstrating
their mesoporous characteristics. The average pore
diameter calculated using the Barrett?Joiner?Halenda
(BJH) method was 2.2 nm, and the Brunauer?Emmett?
Teller (BET) surface area is measured to be 660 m2g?1.
Figure 3 reveals the X-ray powder diffraction (XRD)
patterns of the as-prepared MnO nanoparticles,
composites. In the beginning, the amorphous silica
structure peak at 2θ = 23? of the inert surface of
MnO@mSiO2(Ir)@PEG and H-MnO@mSiO2(Ir)@PEG is
observed. As for the MnO nanoparticles, the cubic
structure with characteristic peaks of (111), (200), (220),
(311), and (311) are well-resolved from the X-ray
of H-MnO@mSiO2(Ir)@PEG nanoparticles, respectively.
Figure 3. X-ray diffraction spectra of MnO, MnO@mSiO2-
(Ir)@PEG, and H-MnO@mSiO2(Ir)@PEG nanoparticles.
PENG ET AL.
’ NO. 5
diffraction (XRD) pattern of MnO@mSiO2(Ir)@PEG and
The hollow MnO NPs are further characterized by
high-resolution TEM (HR-TEM), electron diffraction
(ED), and X-ray photoelectron spectroscopy (XPS).
The HR-TEM images (Figure 4B) and ED pattern (see
inset of Figure 4A) indicate that the hollow MnO
nanoparticles have a lattice spacing of 2.2 Å and still
remain a highly crystalline structure (cubic) similar to
that of the original MnO NCs. The XPS (Figure 4C)
provides the information on the oxidation state of
manganese cations, the results of which indicate that
there is no significant change in the oxidation state
With all data provided (including the XRD spectra), the
etching process developed in this study causes no
changes in either oxidation states or crystallinity.
The results are in stark contrast to previously reported
(þ2 to þ3)10or crystallinity (cubic to amorphous)14
upon forming a hollow structure from solid manganese
oxide nanoparticles. The difference lies in the fact that
the protocol developed in this study exploits low
reaction temperature (∼60 ?C) and short reaction time
(<10 h), such that no redox reaction10and no alterna-
tion of crystallinity14take place.
The finding that EA/NaOH(aq) solution is able to
facilitate the transformation of MnO NCs to a hollow
structure is of fundamental interest and is worthy of
further in-depth investigation. Thus, the associated
mechanism is pursued by conducting a variety of
of all, when only NaOH(aq) is added to execute the
etching process, no hollow-shaped nanoparticles are
produced. As for the second control experiment, only
To our surprise, the Kirkendall effect seems to be
operative and the TEM image of the collected inter-
mediates (see Figure S4A in Supporting Information)
shows irregular morphology. We thus suspect that a
small proton of EA may dissociate, generating the
acetate anions that is able to chelate the metal ion,
Figure 4. (A) TEM image of hollow manganese oxide (H-MnO) nanoparticles. Inset: SAED pattern. (B) High-resolution TEM
imageof H-MnONPs(scalebar:6nm). (C)XPS spectrafor MnOnanocrystalsbefore(blue)andafter (red)theetchingprocess.
(D) Schematic for the evolution of the morphologies of the particles.
PENG ET AL.
’ NO. 5
which then gradually etches MnO from the inner core
via Kirkendall effect. This process should be acceler-
ated under base (e.g., NaOH) catalysis. To test this
hypothesis, we then monitor the etching of MnO NCs
by using sodium acetate (CH3COONa, 2 mM). Similarly,
the results reveal the formation of hollow MnO NPs
(mixed with yolk?shell intermediates) after 24 h reac-
tion times (see Figure S4B). Moreover, during the early
reaction period of ∼10 h, the core?shell?void inter-
mediate is also traceable, as shown by TEM images
displayed in Figure S4C. Evidently, the sodium acetate
also helps formation of hollow MnO NPs, supporting
the proposed chelating mechanism. In comparison to
the etching process using EA/NaOH(aq) solution, how-
ever, the use of sodium acetate gives inferior quality of
the hollow MnO NPs in terms of homogeneity and
particle dispersion (c.f., Figure 4A and Figure S4B in
Supporting Information). The evolution of the mor-
phologies upon etching the particles is schematically
depicted in Figure 4D. Four distinct stages amid the
the core?shell?void intermediate, the yolk?shell
intermediate, and the final hollow structure. The
EA/NaOH(aq) solution serves as a decent reagent,
which undergoes gradual release of acetate anions
to smoothly etch the inner core of MnO via the
In an aim to achieve the multifunctionality of the
nanocomposite, we then move one further step by
incorporating the emissive dye during the sol?gel
process. In this approach, an (EtO)3Si-functionalized
iridium complex (Ir(III) complex; see Figure 1A) is
simultaneously encapsulated into the mesoporous
silica framework by covalent bonding (see Methods
for details), forming H-MnO@mSiO2(Ir)@PEG. Figure S5
of the Supporting Information shows the red phos-
phorescence (λmax= 600 nm) and corresponding ex-
citation spectrum of the as-prepared H-MnO@mSiO2
(Ir)@PEG nanocomposites in both degassed and aera-
ted solution. Note that the phosphorescence of the
Ir(III) complex, due to the short radiative lifetime
promoted by the heavy atom (Ir) spin?orbit coupling
effect, is only quenched 70% from degassed (Φp∼ 0.9,
τp∼ 2.3 μs) to aerated (Φp∼ 0.31, τp∼ 0.80 μs)
by O2, generating singlet molecular oxygen, can be
exploited in photodynamic therapy, while the remain-
ing Φp∼ 0.31 phosphorescence can thus be used for
In the above H-MnO@mSiO2(Ir)@PEG nanocompo-
sites, PEG is incorporated to avoid collapse of the pore
and to increase the colloidal stability. Very recently, Lin
etal. hadreported thatporecollapsinginPBScouldbe
avoided by modification of PEG onto the mesoporous
shell, which effectively masks the surface silanol group
via the formation of a biocompatible layer.26To man-
ifest the PEG modification in the current study,
dynamic light scattering (DLS) has been performed
and the results are shown in Figure S6 of the Support-
ing Information. DLS data of H-MnO@mSiO2(Ir)@PEG
reveal a mean hydrodynamic diameter about 98.4 nm
in PBS solution. Compared to the particle sizes calcu-
lated from TEM images (see Figure 2C and statistics in
FigureS1B), thelargersize measuredbyDLS originates
from the hydration layer of PEG coated onto the sur-
face. Notably, template CTAB is hazardous and less
biocompatible27and should be removed before any
bioapplications. The removal of CTAB can be con-
firmed by zeta-potential measurement.28Without
washing, the adsorption of the cationic surfactant
leads to a positively charged surface of þ50.5 mV.
The gradual removal of the CTAB surfactant after two
ion exchange procedures is reflected from the de-
crease of the zeta-potential measurements, stabilizing
to a negatively charged ?27.7 mV (see Figure S7). To
further demonstrate the successful PEG modification
and surfactant extraction, the results of TGA of
H-MnO@mSiO2 (see red line of Figure 5) reveal a
∼10% weight loss of CTAB, oleic acid, and Ir(III) com-
as clearly shown in Figure 5, much less weight loss of
∼4% is obtained. The 6% difference in weight loss is
then attributed to the removal of CTAB. After PEG
in Figure 5) confirms that PEG is successfully functio-
nalized on the silica surface.
Nowadays, many reports on manganese-related
nanoparticles give various relaxivities, due to different
field strength applied.9?11,13,14,29?33Here, in an aim to
shapes and shell silica porosity conditions of the
nanocomposite, we then systematically measure the
longitudinal relaxivity r1using a 0.47 T Minispec spec-
trometer (see Methods for details) as a function of the
following nanoparticles: MnO, H-MnO, MnO@SiO2
(Figure S8 in Supporting Information), MnO@mSiO2,
and H-MnO@mSiO2with controlled silica shell thickness
Figure 5. Thermal gravimetric analysis (TGA) of
H-MnO@mSiO2(Ir) (CTAB wash), H-MnO@mSiO2(Ir), and
PENG ET AL.
’ NO. 5
around 30 nm. Based on the r1relaxivity value listed in
the highest r1value (0.92) among all titled NPs. H-MnO
NPs possess both inner and outer surface (c.f. outer
surface only for MnO NPs) to interact with water
molecules, rationalizing the enhancement of r1
relaxivity.10,14The trend of r1relaxivity is on the order
of H-MnO@mSiO2(0.2) > MnO@mSiO2(0.16) > MnO@
SiO2(0.07). Evidently, the r1relaxivity value decreases
substantially from 0.17 in MnO NPs to 0.07 in MnO@
SiO2. Although water would be still permeable inside
the amorphous silica shell to contact the Mn(II) ion on
the surface of MnO NPs, the nonporous silica frame-
work may diminish the r1relaxivity by shortening the
mesoporous silica modification species, MnO@mSiO2
as that of bare MnO NCs. We attribute the high r1
relaxivity to the existence of the worm-like nanochan-
nels, such that the water exchanging rate can be
facilitated. Due to additional inner Mn ion surface
layers, the relatively higher relaxivity (0.2) could be
attained in H-MnO@mSiO2. Nevertheless, this value is
still smaller than that of H-MnO (0.92) by more than
3-fold. It is believed that the hydroxyl group on the
surface of MnO might partially participate in the
sol?gel process, forming to a silica layer that blocks
water molecules to reach the surface Mn ion. No
significant decrease of r1relaxivity (0.2) was observed
after incorporating an Ir(III) complex and modifying
PEG onto the outmost surface (H-MnO@mSiO2(Ir)@
PEG). It should be noted that, if CTAB is extracted
before PEG modification, forming H-MnO@mSiO2(Ir)@
PEG* as opposed to regular H-MnO@mSiO2(Ir)@PEG
synthesized here (i.e., PEG modification, followed by
CTAB extraction), the r1value apparently decreases to
easily functionalized on the innernanochannel surface
and thus hampered the diffusion of water from the
surrounding environment to the core part. We have
also carried out a systematic study in an aim to
optimize the r1value using H-MnO@mSiO2and found
that the thickness of both of the core hollow MnO and
mesoporous shell increases. On the other hand, the r1
value seems to reach an optimum value upon forming
hollow MnO with a shell thickness of 30 nm. Further
etching gradually decreases the r1value. In theory, the
r1value will finally close to that of pure water upon
completely etching MnO, forming the hollow meso-
porous silica. For the purpose of their cellular test (vide
infra) and future clinically related application, the
relaxivity of H-MnO@mSiO2(Ir)@PEG was further mea-
and similar r2values (1.75 mM?1s?1) in comparison to
that measured at 0.47 T.
Also, it is noteworthy that the mesoporous silica
shell hasbeen widely usedindeveloping various kinds
of bionanocomposites. Prototypical examples are
those mesoporous shells with the magnetic (T2) or
optical nanoparticle cores that carry drugs for cancer
diagnosis and treatment;28,34?42the outer silica shell
nanoparticles in the physiological environment. In this
study, the H-MnO@mSiO2(Ir)@PEG seems to be a very
promising T1contrast agent and versatile nanocom-
posite for bioimaging and drug delivery. Details of
the relevant applications are elaborated upon as
In Vitro Cellular Testing. First of all, the toxicity of the
nanoplatform is examined prior to the application in
cells or tissue. In this study, the HeLa cell line, derived
from the human cervical cancer cell, is chosen for
cytotoxicity evaluation. The cells are cultured in 90%
minimum essential medium (MEM; Cellgro Herndon,
VA, USA) supplemented with 10% heat-inactivated
fetal bovine serum, penicillin (50 U/mL), and strepto-
mycin (0.05 mg/mL). For cell expansion and senes-
cence induction, the cells are cultured at 37 ?C in a
humidified atmosphere of 5% CO2/95% air and pas-
saged by trypsinization. To examine the cytotoxicity,
various concentrations of nanocomposites, 5, 10, 20,
40, 50, and 100 μg/mL, are added to each HeLa cell
H-MnO@mSiO2(Ir)@PEG, the result of the MTT (3-(4,5-
bromide) test shown in Figure S9 of the Supporting
Information reveals that almost 100% of the cells are
viable even after incubation with a dose of as high as
We then demonstrate a unique three-in-one prop-
erty of the as-prepared H-MnO@mSiO2(Ir)@PEG nano-
magnetic resonance imaging, and PDT. The confocal
microscopy images and fluorescence staining are first
performed to ensure interaction between the as-pre-
pared nanocomposite and HeLa cells. In this experi-
solution and stained with dyes 40,6-diamidino-2-
phenylindole (DAPI) and Alexa Fluor 488 phalloidin
for 24h.As forthe
TABLE 1. Relaxation Properties of the Nanocomposites
0.17 (3 T)
1.75 (3 T)
PENG ET AL.
’ NO. 5
for nucleus and cytoskeleton labeling, respectively.
The confocal image shown in Figure 6A clearly indi-
phorescence wasinternalized into the cells andmainly
resided in the cytoplasm close to the nuclei. Although
the exact location of the particles was not fully deter-
mined, collective images from Z-stack scanning (see
Figure S10 in Supporting Information) indicates that
nearly none of particles are located on the cell mem-
brane and inside the nucleus. Thus, the confocal
imaging sufficiently illustrates efficient labeling and
specific location characters of the H-MnO@mSiO2(Ir)@
PEG. To demonstrate the PDT capability, the HeLa
cells are treated with H-MnO@mSiO2(Ir)@PEG. The
incubated cells with different concentrations of
H-MnO@mSiO2(Ir)@PEGparticles beforeandafter light
exposure were then examined, and the results are
summarized in Figure 6B. To ensure the apoptosis is
solely caused by singlet oxygen, a variety of experi-
ments have been performed, which are categorized as
follows: (A) cells with no nanoparticles and no light
exposure; (B) cells with no nanoparticles but with light
exposure (30 min, 200 mW); (C) cells with 100 μg/mL
exposure; (D) cells with a series of dose-dependent
concentrations from 25 to 100 μg/mL and under light
in all controls (A), (B), and (C) under MTT assay, elim-
nanocomposite toxicity or irradiation of the light
source individually. In (D), as shown in Figure 6B, the
viability of cells after simultaneous treatment of
H-MnO@mSiO2(Ir)@PEG and light drastically decreases
(80 to 14%), which also reveals a dose-dependent
relationship (25?100 μg/mL). The MR signals in T1-
weighted contrast imaging brightened as the concen-
concentration is further confirmed with inductively
coupled plasma mass spectrometry (ICP-MS). Figure 7B
shows the MR images of the collected cell pellets
with or without H-MnO@mSiO2(Ir)@PEG treatment.
is clearly indicative of H-MnO@mSiO2(Ir)@PEG label-
ing capability and could be used for cell tracing.
The combination of these results demonstrates a
promising biocompatible H-MnO@mSiO2(Ir)@PEG
Figure 6. (A) Confocal image of HeLa cell treated with 100 μg/mL MnO@mSiO2(Ir)@PEG. The nucleus, cytoskeleton, and the
nanoparticles are shown in blue, green, and red, respectively. (B) After PDT test, the MTT assay was then performed under
various experimental conditions: (1) EXP(A) cells with no nanoparticles and no light exposure; (2) EXP(B) cells with no
Figure 7. (A,B) Side and bottom view of MR imaging. (A) T1-weighted images of H-MnO@mSiO2(Ir)@PEG as a function of
manganeseoxide.(B)T1-weightedimagesofdifferentconditions. Fromleftto right:PBSbuffer,HeLacells,HeLacellstreated
with 100 μg/mL H-MnO@mSiO2(Ir)@PEG.
PENG ET AL.
’ NO. 5
nanocomposite in phosphorescence imaging, MRI,
and photodynamic therapy.
In summary, several remarks can be pointed out in
this study. First, using EA/NaOH(aq), a new and facile
method to prepare uniform hollow MnO NPs has been
demonstrated. In-depth investigation of the etching
role, which acts as a ligand to chelate the metal (Mn)
ion and then extrude the core MnO via Kirkendall
effect, forming hollow MnO (H-MnO) nanoparticles.
To optimize the biocompatibility of H-MnO NPs, we
further synthesized the H-MnO@mSiO2NPs, in which
the mesoporous silica possesses three distinct topolo-
gical domains that can be independently functiona-
lized: (1) the silica framework, (2) the worm-like
surface. A systematic investigation of the r1relaxivity
property was then carried out among various types of
MnO nanocomposites, andthe resultsshow promising
r1relaxivity for H-MnO@mSiO2NPs. To achieve multi-
functionality, a highly emissive Ir(III) complex, which
serves as both photosensitizer and the luminescent
via the sol?gel chemistry. The worm-like nanochan-
diffusion of oxygen but also increase water perme-
ability to interior hollow manganese oxide core, en-
hancing theT1signal.Finally,the PEG,a biocompatible
polymer, is then anchored on the outermost surface to
maintain the pore structure. Also, its nonfouling prop-
erty avoids protein adsorption and then bypasses the
RES system in in vivo applications. Thus, the results
presented herein provide a facile and novel approach
for developing trifunctional T1MRI contrast agents
inside a mesoporous silica nanoparticle.
Chemicals. 1-Octadecene (technical grade, 90%, Acros), oleic
acid (90%, Acros), manganese chloride tetrahydrate (MnCl2?
4H2O, 99%, Aldrich), hexanol (98%, Acros), Triton X-100 (Acros),
tetraethyl orthosilicate (98%, Acros), ammonium hydroxide
(28?30 wt %, Fluka), 2-[methoxy(polyethyleneoxy)propyl]tri-
methoxysilane (PEG500-silane, Mw= 460?590, tech-90, Gelest),
nium bromide (CTAB, 99%, Acros), sodium carbonate (Na2CO3,
Showa), triethoxysilane (HSi(OEt)3,AlfaAesar),platinum divinyl-
tetramethyldisiloxane (Pt(dvs), Aldrich), sodium hydroxide, eth-
without further purification.
Ir(III) Complex Sensitizer. The highly emissive, alkene-functio-
nalized Ir(III) complex [Ir(piq)2(pp-butylene)] was prepared by
treatment of [(piq)2Ir(μ-Cl)]2 with the pyridyl pyrazole (pp-
butylene)H and Na2CO3in refluxing 2-methoxyethanol. The
(EtO)3Si-functionalized Ir(III) complex [Ir(piq)2(ppTES)] was sub-
sequently prepared using [Ir(piq)2(pp-butylene)], triethoxysi-
lane, and Pt(dvs) in toluene. After stirring at reflux for 15 h,
the solvent was evaporated under vacuum and the unreacted
silane reagent was removed by repeated hexane washes.
Spectral data of [Ir(piq)2(pp-butylene)]: MS (FAB,193Ir) m/z =
798 (Mþ);1H NMR (400 MHz, acetone-d) δ = 9.06?9.00 (m, 2H),
8.3 (dd, 2H, JHH= 13.2, 12 Hz), 7.96?8.02 (m, 2H), 7.72?7.84 (m,
7H), 7.6 (d, 1H, JHH= 6.8 Hz), 7.53 (d, 1H, JHH= 6.4 Hz), 7.42?7.46
(m, 2H), 7.02 (t, 1H, JHH= 16.8 Hz), 6.90?6.97 (m, 2H), 6.82 (t, 1H,
JHH= 22.4 Hz), 4.83 (d, 1H, JHH= 12.4 Hz), 2.54?2.61 (m, 2H),
2.24?2.3 (m, 2H). Spectral data of [Ir(piq)2(ppTES)]: MS(FAB,
193Ir) m/z = 962 (Mþ);1H NMR (400 MHz, CDCl3) δ = 8.97?8.89
(m, 2H), 8.23 (dd, 2H, JHH=14.2, 8.0 Hz), 7.81?7.75 (m, 2H),
1H), 6.39 (d, 1H, JHH= 7.2 Hz), 3.67?3.79 (m, 6H; OCH2Me),
2.59?2.66 (m, 2H), 1.54?1.64 (m, 2H), 1.15?1.31 (m, 11H),
0.56?0.63 ppm (m, 2H).
MnO Nanocrystals. Manganese oxide nanocrystals (NCs) were
prepared by the method described previously with some
modifications.21Manganese oleate complex is prepared by
the reaction of MnCl234H2O and oleic acid in methanol under
basic conditions. Typically, 1.24 g of the manganese oleate is
used and dissolved in 10 g of 1-octadecene. The mixture
and oxygen. The reaction mixture was subsequently treated
with a definitive temperature program. First of all, the solution
was rapidly heated to 200 ?C at a rate of 5 ?C/min. The solution
before cooling to room temperature. Solid samples were col-
redispersing the precipitate with hexane and isopropyl alcohol
several times. Finally, the purified MnO nanocrystals are dis-
persed in 10 mL of hexane.
H-MnO Nanocrystals by Etching Process. Prior to the etching
process, phase transfer of MnO nanocrystals dispersed in
hexane was preceded as follows: First, dried manganese oxide
NCs were dissolved in chloroform. Two milliliters of the NC
solution (10?20 mg/mL) was mixed with 100 mg of cetyltri-
methylammonium bromide (CTAB) and 20 mL of water. The
mixture was then stirred vigorously, and the formation of the
oil-in-water microemulsion appeared with a turbid brown solu-
tion. Then the chloroform solvent was boiled off from the
solution, resulting in a transparent black MnO/CTAB solution.
The solution was filtered through a 0.44 μm syringe filter to
remove any large aggregates or contaminants. The etching
process was performed by adding 0.5 mL of 0.4 M NaOH
solution and 3 mL of ethylacetate to a mixture of 29.5 mL of
and stirred for 10 h. Resulting H-MnO NPs were retrieved by
repeating the procedures of centrifugation and then washing
by repetition of dispersion in distilled water several times.
MnO@SiO2Nanoparticles. MnO nanocrystals with amorphous
silica modification were prepared from reverse micelles by
using a modified procedure we reported previously.22
MnO@mSiO2(Ir)@PEG and H-MnO@mSiO2(Ir)@PEG Nanoparticles. For
coating mesoporous silica shells onto MnO nanocrystals, an-
other 200 mg of CTAB, 0.5 mL of 0.4 M NaOH solution, 3 mL of
ethanol, and 0.5 mL of tetraethylorthosilicate (TEOS) were
added to a mixture of 29.5 mL of water and MnO/CTAB solution
in sequence. The mixture was heated to 60 ?C under stirring.
After 30 min, 2 mg of Ir(III) complex was added and the solution
was stirred for another 6 h. The as-synthesized materials were
centrifuged and washed with ethanol. As for the formation of
the hollow MnO core (H-MnO@mSiO2(Ir)), the etching process
mentioned previously was applied. Prior to the extraction of
PENG ET AL.
’ NO. 5
surfactants (CTAB) from the NPs, surface modification of poly-
(ethylene glycol) (PEG) proceeded as follows: 2-[methoxy-
(polyethyleneoxy)propyl]trimethoxysilane (30 μL) was added
the samples were centrifuged several times to remove the
unreacted chemicals. To avoid the MnO dissolution that occurs
and efficient ion exchange method where the as-synthesized
MnO@mSiO2(Ir)@PEG (H-MnO@mSiO2(Ir)@PEG) NPs are trans-
ferred to 50 mL of ethanol containing 0.3 g of NH4NO3and kept
at 60 ?C for 2 h. The extraction step was repeated twice to
remove the surfactants. After 72 h of dialysis, the final product,
MnO@mSiO2(Ir)@PEG (H-MnO@mSiO2(Ir)@PEG), was prepared
and ready for use.
Confocal Fluorescence Imaging. For confocal microscopic obser-
vation, the HeLa cell were seeded in a 6-well plate with 5 ? 104
cell/well density in 2 mL of serum-free culture medium to
promote the uptake of nanoparticles. After 2 h incubation time
with 100 μg/mL MnO@mSiO2(Ir)@PEG, cells were washed three
times with PBS and then fixed with 4% paraformaldehyde in
PBS. The cells were washed twice with PBS and then incubated
in 0.1% Triton X-100 for 5 min. In order to study confocal
fluorescence imaging, 40,6-diamidino-2-phenylindole (DAPI,
Molecular Probes) and Alexa Fluor 488 phalloidin (Invitrogen)
The cells were stained with 5 μg/mL Alexa Fluor 488 phalloidin
in 3% BSA for 30 min and 10 μg/mL DAPI for 5 min. The cells
were washed twice with PBS and observed by a Zeiss LSM710
NLO confocal spectral microscope equipped with 63X (P-APO,
1.40 oil immersion) objective, and using 405 nm diode laser,
488 nm argon laser, and 543 nm He?Ne laser as excitation
In Vitro Cytotoxicity. The cell viability was analyzed by using a
nyltetrazolium bromide (MTT, Roche). The HaLa cells were
seeded in a 24-well plate with 5 ? 104cell per well in 90%
minimum essential medium (MEM; Cellgro Herndon, VA, USA)
supplemented with 10% heat-inactivated fetal bovine serum,
penicillin (50 U/mL), and streptomycin (0.05 mg/mL). To con-
5, 10, 20, 40, 50, and 100 μg/mL. After 24 h of incubation, wells
were washed twice with PBS and then incubated with 500 μL of
diphenyltetrazolium bromide) agent. After 3 h of reaction time,
culture medium was removed and replenished with 300 μL of
dimethyl sulfoxide (Sigma-Aldrich) to dissolve the purple MTT-
fluorescence (VersaMax Microplate Spectrophotometers; Mo-
lecular-Devices). All of the conditions were done three times.
PEG was analyzed by PDT for cytotoxic effect. To promote the
plate with 5 ? 104cell/well density in serum-free culture
medium. To observe the dose-dependent relationship, four
different dosages were added to the cell sample: 0, 25, 50,
twice with PBS and replenished with culture medium. Each
sample was treated under a fiber optic halogen light source at
200 mW for 30 min, which can eliminate the possible celluar
damage caused by heat. The power of the light source was
measured by a power meter. The treated cells were incubated
with 500 μL of culture medium with 10% MTT (3-(4,5-di-
after being washed twice with PBS. After 3 h reaction time,
culture medium was removed and replenished with 300 μL of
dimethyl sulfoxide (Sigma-Aldrich). The absorbance was mea-
sured at 595 nm with fluorescence (VersaMax Microplate Spec-
trophotometers; Molecular-Devices). All of the conditions were
done three times.
Relaxivity Measurement. Measurements of r1and r2relaxation
times were made at 40 ?C using a 0.47 T Minispec spectrometer
(Bruker Minispec mq series relaxometer); r2relaxation times
were determined using a Carr?Purcell?Meiboom?Gill (CPMG)
sequence, recycle time 10 s, eight averages with phase cycling,
and 180? pulse separation of 1 ms. Monoexponential fitting
was performed to even echoes over 250 ms acquisition
window. The r1 relaxation was estimated using inversion
recovery techniques, recycle time 10 s, four averages with
phase cycling, and eight inversion times logarithmically
spaced over the interval 0?2000 ms. Linear regression be-
tween r1and r2and manganese concentration was performed
using standard techniques.
MRI Cell Sample Measurement. MRI was performed using a
clinical 3 T MR system (Signa Infinite Twinspeed, GE Healthcare,
a homemade water tank. The tank was then placed in an 8
channel head coil. Two dimension T2-weighted fast spin echo
pulse sequences were used (TR/TE = 550/13 ms). The slice
thickness was 1.5 mm with a 0.2 mm gap and the field of view
(FOV) was 14 ? 7 cm. The matrix size is 288 ? 192. Total scan
time was 2 min and 46 s at the NEX of 3. The images were then
analyzed at the workstation provided by GE Healthcare
(Advantage workstation 4.2).
Instrument Information. The as-prepared nanoparticles were
characterized with a transmission electron microscope (Hitachi
H-7100, 80kV),powder X-ray diffractometer(modelPANalytical
X'Pert PRO), and high-resolution transmission electron micro-
scope (JEOL JEM-2100F, 200 kV) including a CCD camera with
Diffpack program. X-ray photoelectron spectrometry (XPS/
ESCA) was done with a PHI 5000 VersaProbe scanning ESCA
microprobe (ULVAC-PHI, Japan) using a microfocused, mono-
chromatic Al KR X-ray (25 W, 100 μm). Excitation and emission
spectra were both recorded on an Edinburgh (FS920) fluori-
meter. Hydrodynamic radii and surface charges were measured
with a Zetasizer (Malvern Zetasizer 3000 HS).
Acknowledgment. This work is supported by the National
Science Council, Taiwan. We thank Mr. Wei Chen for N2adsorp-
tion?desorption isotherm measurement.
Supporting Information Available: TEM image of MnO NCs
dispersed in water, Kirkendall intermediates, size-controlled
H-MnO@mSiO2(Ir)@PEG, and MnO@SiO2nanoparticles, histo-
gram analysis of H-MnO@mSiO2(Ir)@PEG, excitation and emis-
sion spectra, DLS data and zeta-potential data of H-MnO@
mSiO2(Ir)@PEG nanoparticles, MTT assay results and CLSM Z-
stack scanning images. This material is available free of charge
via the Internet at http://pubs.acs.org.
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