Photo-switchable nanoporous silica supports for controlled drug delivery

Article abstract of DOI:10.1039/c8nj00267c

A photo-responsive ligand 7-[(3-triethoxysilyl)propoxy]coumarin (C) was grafted on the surface of a mesoporous silica SBA-12 material. The obtained functionalized support SBA-12_C was used as an effective light-controlled storage/release system of the anti-inflammatory drug naproxen. Irradiation with UV light at 365 nm induces the photo-dimerization of the coumarin on the surface, giving a dimer connected by a cyclobutane ring, leading to pore closure. However, irradiation with UV light of a shorter wavelength, 254 nm, leads to the cleavage of the dimers, opening of the pores, and the guest drug molecules can be released from the pores. The release of the drug was studied in two types of media, a simulated body fluid at pH = 7 and a simulated gastric fluid at pH = 2. The prepared materials were characterized by high resolution transmission electron microscopy (HR-TEM), nitrogen adsorption/desorption, infrared spectroscopy (FT-IR), thermoanalytical methods (TG/DTA) and liquid and solid-state NMR spectroscopy. The amount of released drug was monitored by HPLC chromatography at defined time intervals. The samples with pores closed by coumarin dimers were tight enough to show premature release of the drug from the sample. After light-driven pore opening, the amounts of released naproxen from coumarin modified mesoporous silica were different, depending on the pH conditions of the release media.

Full text of DOI:10.1039/c8nj00267c

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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The photo-switchable nanoporous silica support for controlled
drug delivery
Vladimír Zeleňák*a, Eva Beňováa, Miroslav Almášia, Dáša Halamováa, Virginie Hornebecqb and
Viktor Hronskýc
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A photo-responsive ligand 7-[(3-triethoxysilyl) propoxy] coumarin (C) was grafted on the surface of mesoporous silica SBA-
12 material. The obtained functionalized support SBA-12-C was used as an effective light-controlled storage/release
system of the anti-inflammatory drug naproxen. Irradiation with UV light of 365 nm induces the photo-dimerization of the
coumarin on the surface giving a dimer connected by cyclobutane ring, leading to the pore closure. However, irradiation
with shorter UV light, 254 nm, leads to the cleavage of the dimers, opening of the pores, and the guest drug molecules can
be released from the pores. The release of the drug was studied into two types of media, the simulated body fluid with pH
= 7 and simulated gastric fluid with pH = 2. The prepared materials were characterized by high resolution transmission
electron microscopy (HRTEM), nitrogen adsorption/desorption, infrared spectroscopy (FT-IR), X-ray scattering (XRD) and
thermoanalytical methods (TG/DTA). The amount of the released drug was monitored by HPLC chromatography in defined
time intervals. The samples with pores closed by coumarin dimers were tight enough to show a premature release of the
drug from the sample. After light-driven pore opening, the amounts of the released naproxen from coumarin modified
mesoporous silica were different, depending of the pH conditions of the released media.
www.rsc.org/
attention as drug delivery systems since they possess the
following unique structural features: (i) tunable particles sizes
and morphology, (ii) uniform and tunable pore sizes, (iii) high
1. Introduction
The growing interest for finding new, more efficient and
reliable methods for treatment of human diseases and for
more efficient drug administration, has induced a huge
research devoted to the design and synthesis of new
functional hybrid materials for controlled drug delivery. The
design of site-specific and stimuli-responsive controlled drug
surface area and large pore volume for efficient encapsulation
and high loading capacity, (iv) high thermal/chemical stability
compared to other polymer-based DDSs, (v) two tunable
functional surfaces: an inner surface in the pore channels and
the outer surface of the particle allowing
a selective
functionalization, (vi) unique porous structures without any
interconnections allowing for a perfect capping essential for
delivery systems (DDSs) is of major interest for researchers
1,2
worldwide
.
Mesoporous silica nanoparticles (MSNs) appear
zero premature release and (vii) good in vivo biocompatibility
8-10
as appropriate materials because they are extremely effective
solid supports which can be synthesized with an adjustable
size, pore volume and pore diameter and which are suitable
for drug storage and delivery due to their stability and no
and hemocompatibility
.
Moreover, MSNs prepared by sol-
gel process are biodegradable. Silica dissolves in the body
within the days to weeks. The biodegradability is dissolution
only with no enzymatic degradation.11-13
cytotoxicity 3
.
MSNs can be modified by various organic groups and so far,
MSNs offer a biocompatible multifunctional platform with
intrinsically high surface area and porosity capable of
delivering large amounts of chemotherapeutic agents4, drugs
for osteoporosis treatment5, antibiotics6 and other drug types,
they have successfully been used as efficient cell markers and
14,15
also for regulated drug-delivery rates
.
Interestingly, the
modification by organic functions can be achieved both onto
the pore walls or the external surface. In this context, hybrid,
surface modified MSNs have recently been devised with
triggering functions and used as nanocarriers for cargo release
7
.
including hydrophobic drugs
MSNs have received growing
upon suitable stimulus. Several thermal-16, redox 17,18, pH-19,
-
bio-20, magnetic-21, photo-responsive22, conformational
conversion23 capping molecules and polymers24 have already
been used to control the opening and closing of the
mesopores to release the cargo molecules on demand.
Moreover, the drug delivery systems with dual action, were
published recently.25,26
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An irradiation of the surface of functionalized MSNs with a temperature. The porous SBA-12 was obtained by calcination
light of characteristic wavelength is possible strategy for of as-synthesized SBA-12 in an air flow at 500 °C. The
controlling the release of the cargo from the particles. For calcination procedure was as follows: 5g of the sample was
example,
when
MSNs
were
functionalized
with heated to 150 °C with heating rate 3°C/min and the sample
mercaptopropyl ligands and the pores were loaded with was held at this temperature for 3 hours. Subsequently the
sulforhodamine, an exposure of the system to visible light temperature was increased to 500 °C by the heating rate
triggered the release of the entrapped molecules due to 1°C/min and the sample was held at this temperature for 7
photodegradation of the chemical groups of mercaptopropyl.27 hours. In the last step the sample was cooled down to room
It was suggested that this approach can be utilized to deliver temperature with the cooling rate 3°C/min.
anti-cancer drugs.
2.1.2.
Synthesis
of
photo-responsive
ligand
7-[(3-
In our recent work, we studied controlled drug release from
MCM-41 modified by biocompatible photo-sensitive cinnamic
triethoxysilyl)propoxy]coumarin.
acid derivative 28
Herein, we report the design and properties
.
7-[(3-triethoxysilyl)propoxy]coumarin was synthesized by two-
step reaction described below. The scheme of the reaction is
depicted in Fig.2.
of other functional light-driven system for controlled release of
naproxen, built from mesoporous support SBA-1229 modified
with coumarin derivate (Fig. 1). Coumarins can undergo a
photo dimerization by either [4+4] or [2+2] cycloaddition
mechanism and they also can undergo the reverse reaction,
i.e. photo cleavage. When the coumarin derivative is irradiated
with UV with wavelength λ = 365 nm, the pores of MSNs are
closed and quest molecules are locked inside the pores (Fig. 1).
After the irradiation with UV light of shorter wavelength λ =
254 nm cleavage of the coumarin dimer takes place and pores
of SBA-12 are opened resulting in the release of guest
molecules.
Fig. 2 Scheme of synthesis of 7-[(3-triethoxysilyl) propoxy] coumarin.
Step 1: Synthesis of 7-allyloxycoumarin (1)
In a typical synthesis, 3.24 g (20 mmol) of umbelliferon was
dissolved in 100 cm3 of acetone and then 4.15 g (30 mmol) of
potassium carbonate was added. Subsequently 6.05 g (50
mmol) of allyl bromide was added dropwise under stirring. The
reaction suspension was stirred and refluxed at 70 °C for 12
hours. The resulted product was isolated after filtration of the
reaction mixture and its evaporation under the reduced
pressure. Final product was purified by recrystallization from
hot ethanol, to yield 3.98 g of 1 corresponding to 98.6 % yield
Fig.
1 Scheme of prepared coumarin derivative and photo-dimerization reaction
based on umbeliferon. 1H and 13C NMR spectra of
1 with
between two molecules.
corresponding assignments of hydrogen and carbon atoms are
depicted in Fig. S1 and S2 in Supplementary material.
1H NMR (400 MHz, CD3OD): δ 3.30 – 3.32 (k, CD3OD) + 4.86 (s,
CD3OD); 4.64 (td, 2H, H11, J11-13 = 1.6 Hz, J11-12 = 3.3 Hz); 5.28 (ddd,
1H, H13, J13-11 = 1.6 Hz, J(13-13)gem = 3.3 Hz, J(13-12)cis = 10.6 Hz); 5.41
(ddd, 1H, H13, J13-11 = 1.6 Hz, J(13-13)gem = 3.3 Hz, J(13-12)trans = 17.3 Hz);
6.05 (ddt, 1H, H12, J12-11 = 3.3 Hz, J(12-13)cis = 10.6 Hz, J(12-13)trans = 17.3
Hz); 6.22 (d, 1H, H3, J3-4 = 9.5 Hz); 6.87 (d, 1H, H8, J8-6 = 2.4 Hz); 6.91
(dd, 1H, H6, J6-8 = 2.4 Hz, J6-5 = 8.6 Hz); 7.50 (dd, 1H, H5, J5-4 = 1.4 Hz,
J5-6 = 8.6 Hz); 7.84 (dd, 1H, H4, J4-5 = 1.4 Hz, J4-3 = 9.5 Hz) ppm.
13C NMR (100 MHz, CD3OD): δ 49.05 (CD3OD); 70.4 (C11, CH2); 102.6
(C3, CH); 113.5 (C6, CH); 114.1 (C10, CH); 118.3 (C13, CH2); 130.5 (C5,
CH); 134.0 (C12, CH); 145.8 (C4, CH); 157.1 (C9, CH); 163.3 (C2, C=O);
163.6 (C7, CH) ppm.
2. Experimental
All chemicals used in the syntheses were obtained by Sigma-
Aldrich and Across Organics companies in the highest purities
and used without further purification. Anhydrous solvents
were obtained after standard procedures described in
literature30 and stored over molecular sieves. 7-[(3-
triethoxysilyl) propoxy] coumarin was prepared by the
combination of chemical reactions described in the
literature31,32 and purified by liquid chromatography.
2.1. Synthesis and functionalization of the samples
2.1.1. Synthesis of mesoporous silica SBA-12
IR (KBr technique, cm-1): υ(CH)ar 3050(w), 2945 (w); υs(CH2) 2980
Mesoporous silica SBA-12 was synthesized using the reactants
TEOS : Brij76 : HCl : H2O with following molar ratio 1 : 0.133 :
3.67 : 124.23 In the typical synthesis, 4 g of surfactant Brij 76
was dissolved in 20 g of distilled water. Then 80 g of HCl (2 M)
was added and the solution was stirred at 50 °C until it became
homogeneous (approximately 3h). Then 8.8 g of TEOS was
added dropwise and the mixture was stirred for 20 h at the
same temperature. The white solid product was filtered off,
washed with distilled water and dried at laboratory
(w); υ(C=O) 1714 (s); υ(C=C)ar 1607 (s) (abbreviations: as
=
asymmetric, s = symmetric, ar = aromatic, aliph = aliphatic, s =
strong, m = medium, w = weak, br = broad).
Step 2: Synthesis of 7-[(3-triethoxysilyl)propoxy]coumarin (2)
5.05 g (24 mmol) of
1
was dissolved in 5 cm3 of DMC (dimethyl
carbonate) at 0 °C. After the dissolution, the temperature of
the mixture was left rise to room temperature during the
stirring and subsequently 0.05 cm3 (0.11 mmol) Pt(dvs)
2 | J. Name., 2012, 00, 1-3
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(Karstedt’s catalyst) and 20.54 g (75 mmol) of triethoxysilane media: a simulated gastric fluid (HCl, pH = 2) and a simulated
were added at laboratory temperature. The reaction mixture body fluid (NaCl, 0.9 %, pH = 7.4). Typically, 0.2 g of SBA-
was stirred at laboratory temperature for 15 hours. The course 12_C_N (open or close configuration) were dispersed in 10 cm3
of the reaction during the time was monitored by TLC. After 15 of appropriated fluid. Then, 0.5 cm3 of the suspension was
hours the solvent was evaporated under vacuum to yield 2 as a sampled using automatic pipette after 1, 2, 3, 4, 5, 6, 8, 24, 30
yellow oil. After purification by column chromatography on and 48 hours and nanoparticles were separated by
silica gel (300 g silica gel, eluent hexan:ethylacetate / 3:1 / v:v) centrifugation. The released amount of naproxen was analysed
colourless oil was obtained with yield 8.21 g corresponding to using HPLC.
95.11 % based on
1. 2 with
1H and 13C NMR spectra of
2.2. Methods and characterization
corresponding assignments of hydrogen and carbon atoms are
depicted in Fig. 3.
1H and 13C NMR spectra of the prepared compounds
1 and 2
1H NMR (400 MHz, CD3OD): δ 3.30 – 3.32 (k, CD3OD) + 4.86 (s, were measured in deuterated solvents on a Varian Mercury
CD3OD), 0.92 (t, 9H, Hy, Jy = 8.3 Hz, 1.38 (t, 2H, Hh, Jh = 7.0 Hz), 2.05 Plus 400 FT NMR spectrometer using TMS as the internal
(k, 2H, Hg, Jg = 6.5 Hz), 4.00 (q, 6H, Hx, Jx = 7.0 Hz), 4.17 (t, 2H, Hf, Jf = reference. The multiplicity of the 13C NMR signal concerning
6.6 Hz), 6.35 (d, 1H, Ha, Ja = 9.5 Hz), 6.95 (d, 1H, He, Je = 2.3 Hz), 7.03 the 13C - 1H coupling was determined by the DEPT method.
(dd, 1H, Hd, Jd = 2.3 Hz; 8.6 Hz), 7.62 (d, 1H, Hc, Jc = 8.63 Hz), 7,97 (d, Measured spectra were analysed using MESTREC program.
1H, Hb, Jb = 9.49 Hz) ppm.
High-resolution solid-state MAS NMR measurements were
13C NMR (100 MHz, CD3OD): δ 49.05 (CD3OD); 7.37 (Cl, CH2); 18.87 performed at room temperature with a 400 MHz Varian Solid
(Ck, CH2); 23.76 (Cn, 3xCH3); 59.53 (Cm, 3xCH2); 71.55 (Cj, CH2); State NMR spectrometer (Palo Alto, CA, USA). A probe-head
102.18 (Cf, CH); 113.33 (Ch, CH); 113.77 (Cd, CH); 114.06 (Cb, CH); with a 4 mm ZrO2 rotor and a single pulse (SP) sequence
130.33 (Ci, CH); 145.50 (Cc, CH); 157.0 (Ce, CH); 162.94 (Cg, CH), technique was used for the 29Si spectra, cross-polarization (CP)
163.70 (Ca, C=O) ppm.
technique for 13C NMR spectra. The spectra were processed
FT-IR (KBr technique, cm-1): υ(Si-OH) 3600-3000 (br); υ(CH)ar 3080, using the Varian Vnmrj 3.2 and Mestrelab Mnova 9.0 software.
2960; υ(CH2) 2850; υ(C=O) 1684, υ(Si-CH2-R) 1230, 1200; υ(Si-O-R) The 29Si MAS NMR spectra were obtained at a resonance
1112, υ(Si-C) 850 – 750.
frequency of 79.42 MHz. In SP sequence free induction decay
(FID) was recorded after a radio-frequency pulse of 3.6 μs
duration, recycle delay was 30 s, cw high-power proton
decoupling of 100 kHz and MAS rate of 10 kHz. 3500 scans
were accumulated for each spectrum. The chemical shifts were
2.1.3. Modification of mesoporous silica SBA-12
The surface modification of silica was performed using a post-
synthetic procedure, grafting. Typically, 1 g of calcined SBA-12
was suspended in a solution containing 75 cm3 of toluene and
referenced
to
tetramethylsilane
(TMS)
using
tetrakis(trimethylsilyl)silane as an external secondary
standard.
1 g of
2 and the suspension was refluxed for 20 h. Modified
material was filtered off, washed several times with hot
toluene and dried at 80 °C for 24 h. The obtained material was
denoted as SBA-12_C.
The 13C CP MAS NMR spectra were recorded at the resonance
frequency of 100.53 MHz and magic angle spinning rate of 10
kHz. In cross-polarization technique the measurements were
performed with the radio frequency field strength of 90 kHz,
CP contact time 2 ms, acquisition time of 20 ms, relaxation
delay between two consecutive scans 8 s, and SPINAL pulse
high-power proton decoupling of 110 kHz. Number of scans
was 25000. The chemical shifts were referenced to TMS using
adamantane as an external standard.
2.1.4. Loading and release of naproxen
One gram of SBA-12_C was dispersed in 25 ml of ethanol,
irradiated by UV light with λ = 254 nm to obtain open pore
configuration of the substrate and then, 1 g of naproxen was
added. The mixture was stirred slowly at ambient
temperature, under the UV irradiation, for 24 h to reach
equilibrium. The resultant solid was filtered off and washed
with ethanol. The sample was denoted as SBA-12_C_N. The
amount of the loaded naproxen was determined by
thermogravimetric analysis (see paragraph 3.2.) as well as by
high performance liquid chromatography (HPLC). For this
purpose, to 20mg of the sample SBA-12_C_N, 0.15 ml of
hydrofluoric acid was added and mixture was filled with
distilled water to 1 ml. Hydrofluoric acid induced dissolution of
the silica matrix and release of the loaded naproxen into the
solution. The concentration of the naproxen in the solution
was determined by HPLC using acetonitrile : ethanol as mobile
phase (see paragraph 2.2). The determined amount of the
naproxen was 56.7 mg per one gram of the sample SBA-
12_C_N.
The infrared spectra of the samples were recorded using an
Avatar 6700 FTIR spectrometer in the wavenumber range of
4000 – 400 cm-1. The samples were prepared in the form of
KBr pellets with a sample/KBr weight ratio 1/100. Prior the IR
measurements, KBr was dried at 500 °C in an oven for 5 hours
and cooled in a desiccator over silica gel.
Thermal behaviour was studied by thermogravimetry (TGA)
with simultaneous differential thermal analysis (DTA). The
measurements were performed in the dynamic atmosphere of
air (20 cm3.min-1) using STA Netzsch 409-PC apparatus. The
samples with a weight of 20 mg were heated in the
temperature region of 20-900 °C with heating rate of 9 °C.min-
1. The data were evaluated using Proteus Analysis software.
Nitrogen adsorption/desorption isotherms at 77
K were
measured using a Quantachrome Nova 1200e Gas Sorption
System. The adsorption isotherms were collected in a relative
The UV driven release of naproxen from the SBA-12_C_N
carrier was studied at room temperature in two different
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pressure range p/po = 0.005 – 1. The specific surface area (SBET
)
(see Table 1) that the majority of the silicon atoms (60-65%)
of the samples was evaluated using the Brunauer, Emmet and belong to Q4 substructures, which correspond to silicon atoms
Teller equation (BET) from adsorption data in a p/p0 range located in the pore walls. Q2 and Q3 sites indicate that silanol
from 0.05 to 0.2. The pore volumes and pore size distribution groups are mainly located at the surface of the porous
were calculated using density functional theory (DFT) method.
samples. Q2 sites are present with a low concentration of only
The HRTEM micrographs were taken with a JEOL JEM 3010 a few percent (approximately 4%, see Table 1).
(LaB6 cathode) microscope operated at 300 kV. Copper grid After modification of the silica by coumarin derivative,
coated with a holey carbon support film was used to prepare organosiloxane Tm lines appeared in the spectra of the samples
samples for the TEM observations. For the preparation of the SBA-12_C and SBA-12_C_N in the range δ = –50 to –80 ppm,
samples
for TEM a powdered sample was dispersed in ethanol and the surface and presence Si-C bond. As expected, Tm lines are only
suspension was treated in an ultrasonic bath for 10 min.
observed for functionalized samples. The T3 line corresponds
Photo-dimerization and cleavage of dimer formed by photo- to silicon atoms connected to the propyl spacer. The T2 line
responsive C ligand ( ) and MNS grafted by was followed by appears also and corresponds to silicon atoms connected to
corresponding to the attachment of the propyl chain on the
2
2
UV/Vis absorption spectrometry using Specord 350 apparatus propyl spacer with one terminal OH group on Si (see Fig. 4).
in the wavelength range of 200 – 450 nm. UV lamp E-580 (40 The positions, relative intensities and assignment of the Qn and
W) was used as a source of UV radiation at 254 and 365 nm. Tm lines are reported in Table 1. Example of the spectral
UV/Vis measurements were carried out in a quartz cuvette.
decomposition into
a
weighted sum of mixed
Chromatographic analysis was performed on a HPLC consisting Gaussian/Lorentzian lines is shown for the sample of the
of degasser, binary pump and diode array detector (Agilent sample SBA-12_C in Fig. S4 in the Supplementary information.
Technologies 1260 Infinity). LC separation was achieved on Moreover, the 13C NMR spectrum, measured for the sample
reserved phase column Grace Smart RP 18, 150 mm x 4.6 mm, SBA-12_C, is shown in Fig. S5 in the Supplementary
5
μ
m with using acetonitrile: ethanol, 55: 45 (w: w) as mobile information and confirms successful modification of the silica
phase with flow rate 0.9 cm3.min-1. The detection wavelength surface by coumarin derivative.
was set at = 220 nm and analysed injection volume was 20
λ
μl. Quantitative data were collected by using Chemstation
software rev. B.04.03.
3. Results and discussion
3.1. Synthesis
The key step in the preparation of the photosensitive silica
material, was design and the synthesis of [7-(3-
triethoxysilyl)propoxy]coumarin (2), which was used for SBA-
12 modification. The compound was synthesized by two-step
reaction described above (see section 2.1.2.). Corresponding
1H and 13C NMR spectra of final product
2 with corresponding
assignments of hydrogen and carbon atoms are depicted in
Fig. 3a,b and listed in the Experimental section. The
measurements confirmed the successful synthesis of desired
coumarin ligand. Moreover, the synthesized ligand was also
a
characterized by infrared spectroscopy. The IR spectrum of
is shown in Fig. S3 in the Supplementary information.
2
3.2. Characterization of SBA-12, SBA-12_C and SBA-12_C_N solids
Functionalization Evidence through 29Si and 13C NMR
Spectroscopy
The 29Si NMR spectra of samples SBA-12, SBA-12_C and SBA-
12_C_N are presented in Figure 4. To describe spectra, we can
use the common nomenclature in terms of Qn [Si(OSi)n(OH)4–n
;
n = 0, 1, 2, 3, 4] and Tm [RSi(OSi)m-(OH)3–m, m = 0, 1, 2, 3] units,
which differ in the number of organic radical (R) and OH
groups connected to the tetrahedron33. In pure SBA-12 silica
sample distinct resonances corresponding Q4, Q3 and Q2
siloxane sites were observed, that are spread in the δ = –80 to
–120. The relative integrated intensities of these lines indicate
b
Fig.
3
a.) 1H NMR spectra of
2
with assignment of hydrogen atoms to
corresponding signal; b.) 13C NMR spectra of 2 with assignment of carbon atoms
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to corresponding signal.
Textural properties of the prepared mesoporous materials
SBA-12, SBA-12_C and SBA-12_C_N were further studied using
nitrogen adsorption/desorption measurements at 77 K. Fig. 6
shows N2 adsorption/desorption isotherms of the prepared
samples.
All isotherms are characterized by
a
well-defined
adsorption/desorption step between partial pressures p/p0 of
0.2 – 0.4, indicative of the filling of mesopores without a
hysteresis and by a final long plateau. The BET surface areas
(
SBET), DFT pore volumes (VP) and the pore diameters (DP) were
calculated and are summarized in Table 2. As it is obvious from
the table, both the modification of SBA-12 with coumarin
derivate (SBA-12_C) and the loading with naproxen (SBA-
12_C_N) affect SBET, VP, DP and the total adsorption capacity.
Figure 4. 29Si magic-angle spinning solid-state NMR spectra of the samples SBA- Furthermore, materials remain porous even after loading with
12 (1, black curve), SBA-12_C (2, blue curve) and SBA-12_C_N (3, red curve).
naproxen indicating that the pores are not completely filled.
This statement is also confirmed by the value of mesopores
volume 0.181 cm3.g-1 (see Table2) for the sample SBA-12_C_N.
This is due to relatively lower loading amount. The total loaded
amount was 56mg of the drug per 1 gram of silica (see below).
This amount is far below observed e.g. for MCM-41 silica
MCM-41 used in our previous study (loading 399 mg/g)28. This
can be explained more complicated 3D cubic mesoporous
structure of SBA-1229 in comparison with unidirectional
cylindrical pores of MCM-41.
Table 1. Table 2. Deconvolution data of the 29Si NMR spectra for the SBA-12, SBA12_C
and SBA-12_C_N; δ is the isotropic chemical shift and Rel. Int. is the relative integrated
intensity.
Site
SBA-12
SBA-12_C
SBA-12_C_N
Rel.
Rel.
Rel.
δ (ppm)
δ (ppm)
δ (ppm)
int.(%)
int.(%)
int.(%)
Q4
Q3
Q2
T3
-109.8
64.0
-109.2
-100.2
-91.6
-65.8
-56.8
64.3
-109.6
-100.6
-91.7
-65.4
-56.0
60.9
-100.9
32.3
25.2
4.6
31.0
4.2
Infrared spectroscopy
-91.3
3.7
The infrared spectrum of the compound 2, 7-[(3-triethoxysilyl)
̶
̶
̶
̶
2.8
1.8
propoxy] coumarin, is shown in Fig. S3 in the Supplementary
information and the respective wavenumbers and their
assignments are listed in the Experimental section. The broad
band in the range of 3600 – 3000 cm-1 can be attributed to the
T2
3.1
2.1
O-H stretching vibration of the silanol group
υ(Si-OH). The
HRTEM and textural characterisation
stretching vibrations of aromatic C-H groups were observed in
region around 2960 cm-1. The very weak absorption peaks
were observed around 2850 cm-1 corresponding to the C-H
stretching vibrations of ethyl and propyl groups. Moreover, the
The porosity of calcined SBA-12 was firstly studied using
transmission electron microscopy. The TEM images (see Fig. 5)
show a regular hexagonal array of unimodal channels. The Fig.
5a shows view obtained with electron beam parallel to the
channels, while Fig. 5b shows view perpendicular to the pore
direction. Moreover, HRTEM measurements were performed
for surface modified sample with loaded drug, SBA-12_C_N. As
is evident from Fig. 5c, modification and naproxen loading
have no effect on the morphology of mesoporous support.
strong absorption band of carbonyl
υ
(C=O) was observed at
(Si-CH2)
1684 cm-1. Moreover, the presence of alkyl silane
υ
groups was reflected by a strong and sharp band around 1230
cm-1 together with two sharp bands in the range 920 – 800 cm-
1. The presence of alkoxysilne
υ(Si-O-R) group was confirmed
by a strong band at the 1112 cm-1. The absorption band of
υ(Si-C) was observed at 760 cm-1.
Fig. 5 HRTEM images of calcined SBA-12 a) a view parallel to the channels; b) a
view perpendicular to the pore direction; c) a view of the sample SBA-12_C_N
after coumarin modification and naproxen loading.
Fig. 6 Nitrogen adsorption isotherms of prepared materials measured at 77K.
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Table 2 Textural properties of the SBA-12 silica samples
Thermal analysis
The amount of the coumarin derivate grafted on the surface,
the amount of the naproxen loaded in the pores of SBA-12 and
thermal stability of the samples was studied by the techniques
of thermal analysis. The TGA-DTA curves of SBA-12, SBA-12_C
and SBA-12_C_N are shown in Fig.8. The TGA curve of calcined
SBA-12 (green curve) shows a slight weight change (1.1 wt %)
in the temperature range from 50-150 °C due to the release of
physisorbed water molecules. Dehydration process was
accompanied by the endothermic effect at 102 °C on DTA. In
the temperature range 150-550 °C the TGA curve is almost
constant. Above 550 °C slight weight loss was observed (2.11
wt %) corresponding to the condensation and release of
surface OH groups.
SBET
(m2. g-1)
932
VP
DP
SEXT
(m2. g-1)
5.89
VMES
(cm3. g-1)
0.415
(cm3. g-1)
(nm)
3.775
SBA-12
0.624
SBA-12_C
495
413
0.389
0.249
3.279
3.042
9.65
0.224
0.181
SBA-
15.81
12_C_N
SBET - BET surface area, VP - pore volume, DP - pore diameter, SEXT – external
surface area, VMES – mesopores volume
The functionalization of silica framework was also monitored
by the infrared spectroscopy. The IR spectra of SBA-12, SBA-
12_C and SBA-12_C_N are shown in Fig. 7. A relatively broad
band at 3445 cm-1 correspond to silanol stretching vibration
More complicated thermal decomposition was observed for
the functionalized samples SBA-12_C (red curve) and SBA-
12_C_N (blue curve). The weight loss between 50 – 200°C in
the sample SBA-12_C corresponds to the release of solvents
toluene / ethanol loaded into the porous network during the
synthetic procedures. Above the 200°C the TGA curve of SBA-
12_C shows weight change (6.2 wt %) in the temperature
υ
(Si-OH) and stretching vibration υ(OH) of physisorbed water
molecules in the mesochannels of SBA-12. Presence of this
molecules was reflected by the deformation vibration at 1633
cm-1. The characteristic and typical antisymmetric and
symmetric vibrations of Si-O-Si bands at wavenumbers 1078,
807 and 453 cm-1 correspond to the condensed network of
silica.
range from 200
– 600 °C which corresponds to the
The modification of silica by
the infrared spectra of SBA-12_C and SBA-12_C_N samples.
Successful grafting of SBA-12 with was confirmed in SBA-
2 and naproxen was reflected in
decomposition of grafted photo-active coumarin ligands.
Decomposition of coumarin ligand was accompanied on the
DTA curve by weak exothermic peak at 410 °C.
2
12_C and SBA-12_C_N by C-H stretching vibrations at 2980 and
2930 cm-1 and new absorption peak at 1703 cm-1 assigned to
The TGA study of SBA-12_C_N showed two decomposition
steps, first weight loss was observed between 150 – 340 °C
and the second in the region 340 – 700 °C. These two steps can
be attributed to the decomposition of naproxen and to the
degradation of the coumarin ligands. The total mass loss,
attributed to the thermal decomposition of organic
components, was 11.8 wt % and was reflected on the DTA
curve by two exothermic peaks at 462 and 670 °C. The
corresponding amount of the loaded naproxen was calculated
from the mass differences observed for SBA-12_C and SBA-
12_C_N samples in the range 200 – 900 °C. This difference
represents 5.6 wt %, that corresponds to 56 mg of naproxen
per 1 g of the sample SBA-12_C_N.
carbonyl stretching vibration
υ(C=O) of the ligand 2. Other
novel peaks appeared at 1562 and 1508 cm-1 that could be
assigned to υar(C=C) stretching vibrations. Moreover, the
presence of naproxen in the sample SBA-12_C_N was evident
in the IR spectra by the bands at 1727 cm-1
(υ
(C=O)), 1605 cm-1
(
υar(C=C)) and 1228 cm-1
(υ(C-O)). This can be easily perceived
that almost each infrared signal of pure SBA-12 exists in the
infrared spectra of functionalized SBA-12 materials. This
means that the functionalization process does not affect the
main structure of SBA-12.
Fig. 8 TG/DTA curves of calcined carrier SBA-12 (green), coumarin modified
sample SBA-12_C (red) and with loaded naproxen SBA-12_C_N (blue).
Fig. 7 Infrared spectra of SBA-12, SBA-12_C and SBA-12_C_N.
6 | J. Name., 2012, 00, 1-3
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This amount was in very good agreement with the value
obtained by HPLC (see paragraph 2.1.4). The loaded amount is
different than observed in mesoporous silica material MCM-41
which was used in our previous study (loading 399 mg/g)28.
The MCM-41 has a 2D structure while silica SBA-12 has more
complicated 3D cubic mesoporous structure29 and hence the
pores of the SBA-12 material are less available for the guest
molecules.
3.3. Photo-dimerization and photo-cleavage behaviour of
coumarin ligands on SBA-12
Fig. 9 Electronic absorption spectra of [7-(3-triethoxysilyl) propoxy] coumarin
during a) photodimerization (λ = 365 nm) and b) photo cleavage (λ = 254 nm)
processes.
Coumarin undergoes [2π + 2π] cycloaddition when irradiated
with light of a wavelength longer than 300 nm and [2π + 2π]
cycloreversion under irradiation with light of a wavelength
shorter than 300 nm. The aim of our work was to prepare the
porous material with pores that could be purposely opened
and closed by the dimerization of a photoactive ligand
reversibility of photo-dimerization/photo-cleavage
coumarin derivate ligand (
spectrum shows two characteristic absorption bands: the first
one with maximum at = 325 nm is due to a (n – π*)-like
transition caused by the carbonyl function and the second with
maximum at = 280 nm that corresponds to (π – π*)-
transition related to the conjugative π – system.34,35 When this
coumarin derivate ligand is irradiated with UV light at =365
2
. The
of
2
) itself was tested first. Its UV
λ
λ
Fig. 10 Electronic absorption spectra of surface modified sample SBA-12-C during
a) photodimerization (λ = 365 nm) and b) photo cleavage (λ = 254 nm) processes.
λ
nm (40 W), photo-dimerization occurs: the intensity of
absorption band centered at 325 nm decreased with
increasing time of irradiation due to disappearance of double
bonds to form a cyclobutane ring by the dimerization of [7-(3-
triethoxysilyl)propoxy]coumarin monomers (Fig. 9). The time
required to reach the maximum of dimerization of coumarin
derivate ligand was 300 minutes as the spectrum remains
unchanged for higher time of irradiation. Fig. 9 also shows
subsequent irradiation of ligands with UV light of shorter
As found previously for the ligand (
with UV light of = 365 nm leads to a decrease in intensity of
the absorption band centered at 325 nm indicating photo-
dimerization whereas the irradiation at =254 nm induces an
2) alone, the irradiation
λ
λ
increase of the absorption band at 325 nm due to the recovery
of the extended conjugated π – system. The photo-cleavage
process is achieved after 180 minutes (no change in the
absorption spectrum) but it is not totally reversible meaning
that some of the dimers formed by coumarin derivate ligands
grafted on SBA-12 do not revert back to the initial state.
It is to note, that pohotodimerisation and photo cleavage in
coumarin modified sample was slower, in comparison with the
sample modified by derivative of cinnamic acid, studied in our
recent work.28
wavelength
(λ=254 nm). In this case, the intensity of
absorption band centered at 325 nm increased with increasing
time of irradiation indicating the cleavage of the cyclobutane
ring and a return to the initial state of monomers (Fig. 9). The
photo-cleavage at 254 nm proceeds faster than the photo-
dimerization at 365 nm as the spectrum remains unchanged
after 90 minutes. Nevertheless, the absorbance value after 90
minutes of irradiation at 254 nm is close to 0.8 whereas the
one of the initial monomers is close to 1.8. This means that the
photo-dimerization / photo-cleavage process is not totally
reversible. Furthermore, it was also evidenced that the
recovery efficiency decreased with each repetition of the
photo-dimerization / photo-cleavage cycle. This phenomenon
has been found to be the result of a dynamic equilibrium,
which crosslinking and scission occurs at 254 nm.36,37
3.4. Release of naproxen from SBA-12_C_N
The drug release studies were monitored for SBA-12_C_N and
the release profiles are illustrated in Fig. 11. The amount of
naproxen released from silica carrier was investigated by HPLC.
To determine concentration of naproxen, the calibration curve
has been established based on six solutions of different
concentrations of naproxen. The linearity was determined by
3-fold repeating the measurement of each concentration step.
Subsequently a calibration dependence of the peak area of
concentration of naproxen was constructed. Linearity of the
calibration curve was confirmed by the correlation coefficient
R2 = 0.9999 (see Fig. S6 in the Supplementary information).
The Fig. S6 also shows a standard chromatogram trace of
naproxen.
The mentioned two characteristic absorption bands in the UV
spectra were also found in the absorption spectra of
dispersions of coumarin functionalized silica nanoparticles
(Fig.10). To investigate the photochemical properties silica
samples, diluted dispersions of SBA-12_C particles were
prepared and irradiated with UV light of
λ=365 nm
(photodimerization) and of λ=254 nm (photocleavage).
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the solubility of naproxen. Indeed, as naproxen is a weak acid
pKa = 4.15)38,39, its solubility is higher at pH = 7.4 than that at
(
pH = 2 and the drug deprotonation is only possible in solution
with pH = 7.4 (solution of NaCl), leading to highly soluble
sodium salt. These results clearly demonstrated that the
process of opening and closing of pores by UV light was
successful.
Fig. 11 The release profile of naproxen from SBA-12_C_N. a.) simulated body
fluid, pH = 7.4; b.) simulated gastric fluid, pH = 2.
Fig. 11 shows the naproxen release process in simulated body
fluid (pH = 7.4) and in simulated gastric fluid (pH = 2) and, in
both, closed and opened pore configurations. A total loaded
amount of naproxen of 56 mg for 1 g of SBA-12_C_N was
determined (see TGA and HPLC results). This amount was
taken as 100 % in the release studies and used to calculate
percentage of the release amount in the respective intervals.
The results showed small initial burst release of naproxen
during the first hour: a release close to 10 % was evidenced at
pH = 7.4 (for both configurations) and pH = 2 (for open
configuration). For close configuration and pH = 2 the burst
represented 5% (Fig. 11a and 11b). This initial burst is certainly
due to naproxen molecules adsorbed on the external surface
of silica particles.
Fig. 12 Histogram of cumulative release of naproxen in the function of time.
4. Conclusions
In present study, light driven mesoporous composite material
SBA-12_C_N was prepared and studied as potential drug
carrier.
Photo-sensible
coumarin
derivative,
[7-(3-
In open pore configuration the highest release percentage was
58% at pH = 7.4 (not considering 10% initial burst till first
hour). It is evident that even in this case relatively large
amount of the drug was not released till 48 hours. We
suppose, that the possible explanation is that that some pores
were not opened reversibly by irradiation. As it was evidenced
by UV studies (see above), photo-cleavage process is not
totally reversible meaning that some of the dimers formed by
coumarin derivate ligands grafted on SBA-12 do not revert
back to the initial state. This may be a consequence of
crosslinking and scission of grafted ligands.36,37. Moreover,
after opening of the pores, some coumarin molecules on the
surface may interact with the naproxen and in combination
with the complicated 3D pore structure of SBA-12 and may
immobilize some portion of the drug preventing its release to
the solution. Both mentioned factors may contribute to fact,
that after 48 hours still large portion of the drug was not
released.
triethoxysilyl) propoxy] coumarin was synthesized and grafted
on the surface of SBA-12. It was shown, that coumarin
molecules undergo to dimerization reaction leading to closed
pores configuration after irradiation of UV with λ = 365 nm and
its photo-cleavage at = 254 nm. This photo-dimerization was
λ
used as “door-like mechanism” for the investigation of storage
and release processes of non-steroidal anti-inflammatory drug,
naproxen. HRTEM, nitrogen adsorption, infrared spectroscopy
and thermogravimetry were used to monitor the synthetic
steps and confirmed the successful process of modification
and naproxen adsorption. The amount of adsorbed drug was
56 mg per gram of SBA-12_C_N. The release study was
performed into two simulated body fluids with different pH,
gastric fluid (pH = 2) and body fluid (pH = 7.4). The highest
drug release, 68% after 48h (including 10% initial burst), was
observed from the carrier with opened pores configuration in
simulated body fluid (pH = 7.4). At pH = 2, the release of
naproxen from opened pore configuration was lower because
of the drug lower solubility in acidic solution. In the closed
pores configuration, the release of naproxen was hindered,
18.3% and 7.9% at pH = 7 and pH = 2, respectively. Results of
naproxen release clearly confirmed the reversible photo-
dimerization reaction of coumarin molecules grafted on the
surface of SBA-12 and material could be applied for the control
of storage/release of drugs driven by the light as an external
stimulus. The possible application of such UV-driven materials
can be e.g. for topical applications, in medical silica modified
adhesive tapes, which release the drug after the light stimulus.
All results obtained are summarized in Fig. 12. In the time
interval between 1 to 10 hours, observed release behaviours
at pH=7.4 and pH=2 are very similar: in opened pores
configuration, the cumulative release of naproxen lies in the
25-30 % range whereas in closed pore configuration it is much
more smaller (between 3-5 %). In the time interval between 10
to 48 hours, almost no release of naproxen was observed for
samples with closed pores configuration at both pH (7.4 and
2). In opened pores configuration, naproxen was slowly
released from the sample at pH= 7.4 and 2 but a larger amount
was released at pH=7.4 (28%) than at pH=2 (10 %). The pH-
dependence of release process can be explained considering
8 | J. Name., 2012, 00, 1-3
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24 X. Jin, Q. Wang, J. Sun, H. Panezai, S. Bai and X. Wu,
Micropor. Mesopor. Mater., 2017, 254, 77.
Conflicts of interest
There are no conflicts to declare.
25 X. Liu, D. Yu, Ch. Jin, X. Song, J. Cheng, X. Zhao, X. Qi and G.
Zhang, New J. Chem., 2014, 38, 4830.
26 N. Thepphankulngarm, P. Wonganan, Ch. Sapcharoenkun, T.
Tuntulani and P. Leeladee, New J. Chem., 2017, 41, 13823.
27 N. Ž. Knežević, B. G. Trewyn and V. S. Y. Lin, Chem. Comm.,
2011, 47, 2817.
28 E. Beňová, V. Zeleňák, D. Halamová, M. Almáši, V. Petruľová,
M. Psotka, A. Zeleňáková, M. Bačkor and V. Hornebecq, J.
Mater. Chem. B., 2017, 5, 817.
29 Y. Sakamoto, I. Díaz, O. Terasaki, D. Zhao, J. P.-Periente, J. M.
Kim and G. D. Stucky, J. Phys. Chem. B., 2002, 106, 3118.
30 D. Williams, G. Bradley and M. Lawton, J. Org. Chem., 2010,
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31 D. J. Clarke and R. S. Robinson, Tetrahedron, 2002, 58, 2831.
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Acknowledgements
This work was supported by the Slovak Research and
Development Agency under the contract APVV-15-0520 and by
the Scientific Grant Agency of the Slovak Republic (VEGA)
project no. 1/0745/17. The authors thank Dr. V. Girman for
TEM measurements. E. B. thanks to the French Government
for the financial support linked to the implementation of a
joint French-Slovak doctorate. V.Z. thanks the Ministry of
Education, Science, Research and Sport of the Slovak Republic
for the financial support of the TRIANGEL team in the frame of
the scheme „Top Research Teams in Slovakia“.
33 N. Bibent, T. Charpentier, S. Devautour-Vinot, A. Mehdi, P.
Gaveau, F. Henn and G. Silly, Eur. J. Inorg. Chem., 2013, 2350.
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New Journal of Chemistry
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Graphical abstract
Synopsis
Stimuli-responsive drug delivery system consisting of SBA-12 nanoporous silica modified by
photo-switchable coumarin ligand was studied for delivery of non-steroidal
antiinflammatory drug naproxen.