Controlled drug delivery from mesoporous silica using a pH-response release system

Article abstract of DOI:10.1039/c2nj20976d

Mesoporous hollow silica nanoparticles were functionalized with phenanthroline (P-MHS) to prepare a carrier for a host-guest complex. Curcumin was selected as a model drug molecule. The phenanthroline attached to the P-MHS was complexed with Cu²⁺ through a coordination bond. When the Cu ²⁺-P-MHS was exposed to ～pH 5, the curcumin was efficiently released into the aqueous phase within 120 min. This work describes a method for functionalizing the surface of the porous silica nanoparticles in a well-defined manner. The P-MHS carrier exhibited controlled release of a model drug under acidic pH conditions.

Full text of DOI:10.1039/c2nj20976d

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PAPER
Controlled drug delivery from mesoporous silica using a pH-response
release systemw
Dalsaem Jin,a Ji Ha Lee,a Moo Lyong Seo,a Justyn Jaworskiab and Jong Hwa Jung*a
Received (in Victoria, Australia) 21st November 2011, Accepted 14th May 2012
DOI: 10.1039/c2nj20976d
Mesoporous hollow silica nanoparticles were functionalized with phenanthroline (P-MHS) to
prepare a carrier for a host–guest complex. Curcumin was selected as a model drug molecule.
The phenanthroline attached to the P-MHS was complexed with Cu2+ through a coordination
bond. When the Cu2+–P-MHS was exposed to BpH 5, the curcumin was efficiently released into
the aqueous phase within 120 min. This work describes a method for functionalizing the surface
of the porous silica nanoparticles in a well-defined manner. The P-MHS carrier exhibited
controlled release of a model drug under acidic pH conditions.
In general, there are several types of pH-responsive systems,
based on soft matter and inorganic solids.15–18 Soft matter
Introduction
The goal of drug delivery is to administer medicinally active
systems commonly utilize hydrogels, micelles and liposomes, where
molecules with high specificity to diseased cells in a targeted
release involves dimensional changes triggered by swelling/
and controlled manner.1,2 Recently, mesoporous silica nano-
deswelling and stabilizing/destabilizing environments.6–8,10–13
particles were described as an appealing class of drug delivery
Typical inorganic solid systems utilize silica-based nanomaterials,
vehicles, due to their sophisticated design and mode of action.3
where release involves on/off capping, gating, or host–guest inter-
actions (electrostatic19 and coordination bonding20). The driving
Increasing evidence has shown that the nanoparticles are not
cytotoxic and that those in the order of 100–200 nm in
forces of these methods are typically pH-sensitive hydrolysis
diameter can be taken up by cellular endocytosis and transported
or ionizations that change the electrostatic state, polarity,
into acidic lysosomes.2 In addition, stimuli responsive systems
hydrophobicity, or conformation of pH-sensitive polymers,
have shown promise in a variety of applications in biomedical
surfactants, or anchored functional groups. However, examples of
fields.4–13 Stimuli responsive systems are designed to take up
guest molecule release controlled by small pH variations in aqueous
solution are very rare and remain challenging to design.21,22
or release guest molecules in response to external stimuli, like
temperature, pH, light irradiation, ionic strength, redox reagents, or
Herein, we describe a mesoporous silica pH-responsive release
enzymes, etc. These systems are available in diverse physical forms,
including microcapsules,4 micelles,5–8 vesicles9 and liposomes.10–13
system. This system was based on a pH-sensitive functional group
immobilized on the external surface of hollow nanoparticle silica.
These methods have paved the way for precise spatial and temporal
The functional group formed a coordinated bond with a metal
delivery of guest molecules to target sites. Of these stimuli
ion. The formation and cleavage of the metal ion–ligand
responsive systems, the pH-sensitive system is particularly
coordination bonds were sensitive to external pH variations,
interesting. The extracellular pH of tumors is more acidic
because the metal ion was exchanged with an acidic proton.
(pH 5.7–7.8) than that of blood and normal tissues, and the
In the current study, the selected model drug was curcumin
pH values within endosomes and lysosomes reach values as
(or diferuloylmethane), one of the best-characterized chemo-
low as 5.5 and 5.0, respectively.14 Therefore, for some time,
preventative agents.23 Curcumin is extracted from the root
researchers have pursued the development of a finely sensitive
of Curcuma longa and exhibits strong antioxidative, anti-
inflammatory and antiseptic properties.24 Moreover, in acutely
pH-responsive system that would release encapsulated drugs
when passing through a region of low pH (pH 5–7); the
or chronically infected HIV-1 cells, curcumin inhibited purified
stability of this delivery system under physiological conditions
human immunodeficiency virus type 1 (HIV-1) integrase, HIV-1
would presumably reduce potential side effects.
and HIV-2 proteases, and the expression of the HIV-1 long
terminal repeat-directed gene.24,25
a Department of Chemistry and Research Institute of Natural Science,
Gyeongsang National University, Jinju 660-701, Korea.
E-mail: jonghwa@gnu.ac.kr
b Department of Chemical Engineering, Hanyang University,
Seoul 133-791, Korea
w Electronic supplementary information (ESI) available: details of
synthetic data and spectroscopic data. See DOI: 10.1039/c2nj20976d
Results and discussion
Scheme 1 shows the strategy of the pH-responsive release
system of the mesoporous silica surface. Mesoporous hollow
c
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Scheme 1 Schematic mechanism for the pH-responsive system based on host–guest interaction: (a) the preparation of mesoporous-type hollow
silica nanoparticles, (b) the immobilization of the phenanthroline group, (c) the encapsulation of curcumin (3), (d) the complex formation of the
phenanthroline group with Cu2+ by host–guest interaction and (e) release of curcumin molecules by change of pH values.
silica nanoparticles were uniformly covered with immobilized
phenanthroline functional groups attached to the surface by
covalent bonds. Metal ions readily bind to the phenanthroline
groups on the mesoporous surface to form a ‘host–guest’
coordination bond, in which the mesopores are closed. Sub-
sequently, an acidic proton can be exchanged with the metal
ion, and the nitrogen atoms of phenanthroline groups become
protonated; this causes the mesopores to open. Thus, curcumin
Fig. 1 (A) SEM and (B) TEM images of phenanthroline-immobilized
mesoporous hollow silica particles (P-MHS).
molecules harbored within the mesoporous hollow silica nano-
particles can be released into the solution phase with small pH
changes.
to 2 (m/z = 277.13, 319.14), thereby providing evidence that 2
was anchored onto the surface of the silica pfn1articles
(Fig. S2w). After immobilization of 2, the 13C CP/MAS
spectrum of P-MHS contained three peaks in the aliphatic
region and seven peaks in the aromatic region, which were
attributed to the cargo molecule 2 (Fig. S3w). P-MHS was
further confirmed by TEM with the EELS technique (Fig. 2).
The material contained silicon, oxygen, carbon, and nitrogen
components, supporting the idea that phenanthroline was
homogeneously attached to the external surface of the mesoporous
hollow silica nanoparticles. The absorption and emission bands of
P-MHS in the solid state appeared at 330 nm and 451 nm,
respectively; this resulted in a yellow color (Fig. S4w). These
findings suggested that the stopper molecule 2 was attached to
the external surface of the silica nanoparticle. In addition, the N2
adsorption–desorption isotherms obtained at 77 K (Fig. S5w)
The mesoporous hollow silica particles were prepared
through the sol–gel process with an alanine-based amphiphile
1 for a template (Scheme S1w) and tetraethoxy silane for the
silica precursor.26 The phenanthroline group, used as a stopper,
was attached to the external surface of the mesoporous silica
nanoparticles in a sol–gel grafting reaction (Scheme S2w). The
self-assembled 1 template was removed by ethanol extraction;
then, the silica particles obtained in the sol–gel reaction were
characterized by transmission electron microscopy (TEM),
scanning electron microscopy (SEM), BET isotherms and
powder X-ray diffraction (PXRD).
Fig. 1 shows the SEM and TEM images of silica particles
after phenanthroline 2 immobilization with a covalent bond.
The phenanthroline-immobilized mesoporous hollow silica
nanoparticle (P-MHS) was a spherical structure, with a
100–150 nm outer diameter after immobilization of 2, in which
the silica shell had a worm-like structure. The IR and TOF-SIMS
results were consistent with bond formation; the IR spectrum of
P-MHS showed strong new bands at 3200, 3010, 1720, 1600, 1475
and 1420 cmÀ1, which originated from molecule 2. This was
consistent with 2 residing on the silica particle (Fig. S1w). The
TOF-SIMS spectrum of P-MHS displayed fragments attributable
Fig. 2 (a) Bright-field image of P-MHS. Elemental (b) Si mapping,
(c) O mapping, (d) C mapping and (e) N mapping of P-MHS by TEM
with EELS technique. Scale bars are 30 nm.
c
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New J. Chem., 2012, 36, 1616–1620 1617

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showed a typical type IV isotherm; in this, the observed step
could be related to nitrogen condensation inside the meso-
pores by capillarity. The pore size and surface area of MHS
shows 4.9 nm and 620.03 m2 gÀ1, respectively whereas the pore
size and surface area of P-MHS shows 4.7 nm and 448.66 m2 gÀ1
,
respectively. The phenanthroline group as a stopper was attached
before calcination. The surfactant exists inside of mesoporous
silica nanoparticles. Therefore, most of the phenanthroline group
may be immobilized to the external surface (Fig. S5w).3e–g A small
amount of phenanthroline may be attached to the wall of the
pore. The PXRD data of P-MHS also revealed that the material
possessed mesopores with d-spacing of 5.2 nm (Fig. S6w).
To include a model drug molecule, curcumin (10 mM) was
added to a dispersed solution of P-MHS (10 mg) and stirred
for 1 h. The final curcumin-loaded P-MHS (C-P-MHS) solid
was isolated by centrifugation and washed with ethanol to
eliminate the residual curcumin. C-P-MHS was characterized
by TGA, fluorometry, FT IR, and solid 13C-NMR. The
emission band of C-P-MHS solid appeared at 451 nm by
fluorometry. Before immobilization of 2, a small amount of
ethoxy groups remains on the surface of the silica nano-
particles. Therefore, the vibrational band at 2960 cmÀ1 was
relatively weaker in comparison to P-MHS. Also, the vibra-
tional bands at 3500 cmÀ1 is due to the existence of –OH
groups on the silica nanoparticles. On the other hand, the IR
spectrum of C-P-MHS showed new bands at 3300, 3050, 1750,
1475 and 1050 cmÀ1, which originated from curcumin (Fig. S7w). In
Fig. 3 Controlled release profile of cargo molecule 3 from C-P-MHS
in the presence of Cu2+ (5.0 mM) by changing pH values.
aqueous phase (Fig. 3). Thus, the Cu2+ bound to the phenan-
throline group on the external surface of C-P-MHS was
decomplexed by acidic protons, which then bound to the
nitrogen atoms of the phenanthroline group, and opened the
pores on the surface of the P-MHS.
Finally, we investigated the releasing capacity of the hollow silica
particles under different pH conditions. The amount of curcumin
(3) released from C-P-MHS was determined by measuring the
fluorescence emission intensity of the supernatant before and after
the addition of acid. The release profiles were expressed in weight
percentages of cargo 3 at different pH values (Fig. 4). The release
rates of cargo 3 from C-P-MHS were strongly dependent on the
pH values of the solution. The release of cargo 3 was negligible for
120 min at pH 7; this indicated that cargo 3 remained in the pores
of the silica particles. The small amount of cargo molecule 3 was
slightly continually released from C-P-MHS until after 120 min at
pH 6.5. However, at pH 6.5, the releasing rate was almost saturated
after 30 min. For the region of this saturation, we think that the
complexation rate between the phenanthroline group and Cu2+
may be faster than that of the decomplexation rate between the
phenanthroline group and Cu2+. This phenomenon is quite similar
to that of observed by the Che group.21 At pH B6, up to 70%
addition, the new vibrational bands appeared at 2700–2300 cmÀ1
.
These represent overtones and combination bands of lower
wavenumber C–C stretching and C–H bending vibrations
that appear in the spectrum by stealing intensity via Fermi
resonance.27 The 13C CP/MAS spectrum of C-P-MHS
included new peaks at 30, 28, 24, 15, 130, 148 and 180 ppm
(Fig. S8w). The estimated loading was 20% of curcumin per
gram of P-MHS (Fig. S9w).
The phenanthroline group can form a complex with Cu2+ at
a 3 : 1 stoichiometry.28,29 Thus, we selected Cu2+ as a stopper
ion. C-P-MHS (10 mg) was suspended in Cu2+ solution
(5 mM). Then, the solid product was isolated by centrifugation
and washed with water to remove the free Cu2+. To determine
whether the phenanthroline group of C-P-MHS had formed a
complex with Cu2+, the fluorescence spectra of C-P-MHS was
observed with and without Cu2+. Fig. S10w showed that the
C-P-MHS had a strong emission in the absence of Cu2+, but
no emission in the presence of Cu2+. This fluorescence
quenching could be explained as a reverse photoinduced
electron transfer (PET) that occurred when Cu2+ had bound
to the nitrogen atoms of the phenanthroline unit (which
behaved as a PET donor).30 These results indicated that Cu2+
had formed a coordination bond with the phenanthroline
groups of C-P-MHS.
To investigate the delivery system of C-P-MHS, we used
luminescence spectroscopy to monitor the release of the cargo
molecule, curcumin (3) upon a change of pH in aqueous
solution. The emission intensity of cargo 3 was negligible
before the triggered release from this system. When the pH
was adjusted from B7 to B5 by addition of 0.1 M HCl, the
emission intensity of curcumin in solution gradually increased,
indicating that cargo molecule 3 had been released into the
Fig. 4 pH dependence of the release profiles of cargo molecule 3 from
C-P-MHS in the presence of Cu2+ (5.0 mM) by treatment of HCl;
(a) pH = 7, (b) 6.5, (c) 6.0 and (d)=5.0.
c
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of cargo 3 was gradually released over 120 min. At pH B5,
approximately 100% of cargo 3 was efficiently released into the
aqueous phase over 120 min. These results strongly indicated
that the acidic protons effectively cleaved the coordination
bonds between Cu2+ and the phenanthroline group attached
onto the external surface of P-MHS. To prove this exchange
reaction, the concentration of Cu2+ remaining in aqueous
solution phase was measured at different pH values by ICP.
20 ppm of Cu2+ exists on C-P-MHS. On the other hand, the
concentration of Cu2+ dissociated from P-MHS to the aqueous
phase by treatment with acidic protons was 15.2 ppm, 7.5 ppm
and 0 ppm for pH 5.0, 6.0 and 6.5, respectively. Thus, the
amount of curcumin 3 released from C-P-MHS was efficiently
controlled by acidity.
products. The products were retrieved by filtration and dried
at 80 1C. 1 was removed by exhaustive solid-liquid extraction
overnight using HCl (0.1 M) with ethanol.
Preparation of phenanthroline-immobilized mesoporous hollow
silica particles (P-MHS)
Compound 2 (100 mg) was dissolved in toluene (10 mL). The
mesoporous hollow silica particle (100 mg) was added as a
solid. The suspension of silica particle was stirred in under
reflux conditions for 24 h in toluene. Then, the collected solid
was washed copiously with toluene (50 mL) to rinse away any
surplus 2 and dried under vacuum.
Loading of curcumin to P-MHS
P-MHS (10 mg) was added to curcumin solution (2.0 Â 10À3 M).
The suspension of P-MHS was stirred for 1 h. Then, Cu2+
(5.0 mM) was added to the mixture of P-MHS and curcumin.
Finally, the collected solid was washed copiously with ethanol
(50 mL) to rinse away any surplus curcumin and dried under
vacuum.
Conclusion
We developed a mesoporous silica-based pH responsive release
system, based on the ‘host–guest’ concept. The curcumin molecules
loaded into pores of P-MHS were effectively released by cleavage of
the coordination bonds between the phenanthroline group of
P-MHS and Cu2+ by acidic protons. Therefore, this system, based
on the complexation of host and guest molecules, may be a
promising method for developing custom-made controlled-delivery
devices specifically triggered by target molecules.
Controlled releasing capacities of C-P-MHS
The releasing capacities of C-P-MHS were observed at 451 nm
(lEx= 330 nm) by a fluorescence spectrophotometer. The pH
values of the suspension of curcumin loaded P-MHS (10 mM)
were adjusted by 0.1 M HCl.
Experimental
Preparation of P-MHS
Phenanthroline derivative 2 (50 mg, 0.05 mmol) was dissolved
in anhydrous toluene (5 mL) to which MHS (100 mg) was
added, and it was stirred under reflux in N2 for 24 h. The
collected solid was washed several times with dichloromethane
and acetone to rinse away any excess 2. P-MHS was obtained
as a solid (100 mg). IR (KBr): 3200, 3000, 1720, 1600, 1475.
Characterization
1H and 13C NMR spectra were measured with a Bruker ARX
300 MHz sepctrometer. IR spectra were obtained for KBr
pellets, in the range 400–4000 cmÀ1, with a Shimadzu FTIR
8400 S instrument, and the MS spectrum was obtained with a
JEOL JMS-700 mass spectrometer. Time-of-flight second ion
mass spectrometery (TOF-SIMS) was analyzed on Model PHI
7200 equipped with Cs and Ga ion guns for positive and
negative ion mass detection. Transmission electron microscopy
(TEM) images were taken with a JEOL JEM-2100 F instrument
operated at 150 kV. Images were recorded on 2 k CCD (Gatan
Inc. USC 1000). Scanning electron microscopic (SEM) images
were taken on a Hitachi S-4500 instrument. The accelerating
voltage of SEM was 5–15 kV and the emission current was
10 mA. All fluorescence spectra were recorded in RF-5301PC
spectrophotometer.
1420 and 1050 cmÀ1
.
Acknowledgements
This work was supported by a grant from the NRF (grant no.
2011-0003118) and the World Class University (WCU) Program
(R32-2008-000-20003-0) supported by Ministry of Education,
Science and Technology, S. Korea. In addition, this work was
partially supported by a grant from the Next-Generation BioGreen
21 Program (SSAC, grant no. PJ009041), Rural Development
Administration, S. Korea.
Preparation of mesoporous hollow silica nanoparticle (MHS)
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with stirring. After continued stirring for another 10 min, the
resultant material was aged at 30 1C for 2 days to get the final
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