Photo-triggered molecular release based on auto-degradable polymer-containing organic-inorganic hybrids

Article abstract of DOI:10.1016/j.bmc.2014.04.034

The photo-triggered molecular release from the organic-inorganic polymer hybrids is presented in this manuscript. Initially, the preparation of the auto-degradable polymer is explained with the photo-cleavable group at the end of the polymer main-chain. T

Full text of DOI:10.1016/j.bmc.2014.04.034

Bioorganic & Medicinal Chemistry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Photo-triggered molecular release based on auto-degradable
polymer-containing organic–inorganic hybrids
Hiroshi Okada a,b, Kazuo Tanaka a, Wataru Ohashi a, Yoshiki Chujo a,
⇑
a Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
b Matsumoto Yushi-Seiyaku Co., Ltd, 2-1-3, Shibukawa-cho, Yao-City, Osaka 581-0075, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The photo-triggered molecular release from the organic–inorganic polymer hybrids is presented in this
manuscript. Initially, the preparation of the auto-degradable polymer is explained with the photo-
cleavable group at the end of the polymer main-chain. The silica-based dye-loaded hybrids containing
these polymers were fabricated. It was found that by UV irradiation, the end capping was removed,
and then the auto-degradation occurs through the polymer main-chain. Finally, the molecular release
of the loaded dyes was accomplished in various media by the UV irradiation. In particular, it was shown
that both of hydrophobic and hydrophilic dyes can be applied in this system.
Received 18 March 2014
Revised 19 April 2014
Accepted 19 April 2014
Available online xxxx
Keywords:
Auto-degradable polymer
Molecular release
Organic–inorganic hybrid
Photoreaction
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
controlled release in long term, the development of robust scaffolds
is desired.
Photo-triggered controlled release is promising technology for
developing a low-invasive therapy with fewer side effects.1–6 Based
on the well-designed inorganic scaffolds, the precise control of the
molecular release has been also accomplished.7,8 By regulating the
timing of the light irradiation, the drug concentration at the local
spot can be readily controlled with site- and time-specificities.
For realizing practical system, a polymer-based scaffold which
can capture the bio-active guest molecules without covalent-bond
linking is a facile candidate as a platform for constructing a drug
carrier.9,8,10–15 In water phase, the hydrophobic moiety in the poly-
mer scaffold can absorb the guests such as drugs or dyes, resulting
in the encapsulation of the guests.16–20 The water-solubility and
stability against the undesired metabolism can be avoided. By
preprogramming the photo-responsive system into the polymer
matrix, the loaded molecules can be released by the trigger through
light irradiation. Furthermore, we can receive the benefits from the
nanomaterials. The site-specific delivery is possible by modulating
the size of the polymer matrices.21,22 Thus, it can be said that the
polymer-based drug carriers are valid under diverse biological
conditions. On the other hand, general polymers have relatively-
low stability under biological conditions comparing to the
inorganic materials. To improve the retention ability and to realize
Organic–inorganic polymer hybrids are classified as a mixture
with a polymer and an inorganic material with the domain size
at nano or molecular scale.23 In general, the hybrid materials can
show advant originated from both organic and inorganic elements.
As a typical instance, by well-mixing with silicate, the robustness
of the materials can be drastically and readily improved.24–30 As
a
result, highly-emissive materials with high stability were
obtained.31,32 However, since the general hybrid materials have
high environmental resistance, very few examples have been
accomplished to offer the molecular release from the hybrids. Next
challenge is to establish the stimuli-responsive release system
using the hybrid materials with a wide variety of the guest mole-
cules. In particular, we aim to receive the function such as wide
encapsulation acceptability originated from organic polymers and
high stability derived from the inorganic element.
Herein, we present the photo-triggered molecular release from
the organic–inorganic polymer hybrids. Initially, we prepared the
auto-degradable polymer with the photo-cleavable group at the
end of the polymer main-chain and the silica-based dye-loaded
hybrids containing these polymers. By UV irradiation, the end cap-
ping is removed, and then the auto-degradation occurs through the
polymer main-chain. Finally, the molecular release of the loaded
dyes was observed in the buffer by the UV irradiation. In particular,
it was shown that both of hydrophobic and hydrophilic dyes can be
applied in this system. This is the first example, to the best of our
⇑
Corresponding author. Tel.: +81 75 383 2604; fax: +81 75 383 2605.
E-mail address: chujo@chujo.synchem.kyoto-u.ac.jp (Y. Chujo).
http://dx.doi.org/10.1016/j.bmc.2014.04.034
0968-0896/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Okada, H.; et al. Bioorg. Med. Chem. (2014), http://dx.doi.org/10.1016/j.bmc.2014.04.034

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H. Okada et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
knowledge, to offer the photo-triggered molecular release from the
organic–inorganic polymer hybrids.
solution. Polymer P1 was dissolved in DMF (20 mL, 200 mg/L),
HCl (0.3 mL) was added, followed by TMOS (3 mL). After stirring
for 5 min, different amounts of a solution of BODIPY (0.21 mM)
in THF (1 mL) or fluorescein (1 mM) in DMF were added to the
reaction solution. The reaction solution was poured into a polypro-
pylene vessel and then heated at 60 °C for 5 days. The glassy green
colored hybrid blocks were obtained. The total amount of the dyes
is corresponded to the dye concentration in the solution in the sol–
gel reaction.
2. Experimental section
2.1. General
1H NMR and 13C NMR spectra were measured with a JEOL EX-
400 (400 MHz for 1H and 100 MHz for 13C) spectrometer. Coupling
constants (J value) are reported in hertz. The chemical shifts are
expressed in ppm downfield from tetramethylsilane, using residual
chloroform (d = 7.24 in 1H NMR, d = 77.0 in 13C NMR) as an internal
standard. MASS spectra were obtained on a JEOL JMS–SX102A. UV–
vis absorption spectra were obtained on a SHIMADZU UV3600
spectrophotometer using 1 cm path length cell. Luminescent spec-
tra of the obtained hybrids were measured by a HORIBA JOBIN
YVON FluoroMax-4 fluorescence spectrometer. All reagents were
obtained from commercial sources and used as received without
further purification.
2.6. UV irradiation
The reaction mixture and hybrids were irradiated with a trans-
illuminator, LMS-20E (365 nm 20 nm, 6.5 mW/cm2), at 25 °C in
open air for each time above 10 cm on the stage.
3. Results and discussion
The chemical structure and molecular release based on the
hybrid material containing the photo-induced auto-degradable
polymer are shown in Scheme 1.33–39 By UV irradiation, the o-
nitrobenzyl ether moiety is released, followed by the generation
of the amino group. Electron donation of the amino group induces
the release of the monomer unit at the end of the main-chain,
resulting in the generation of the new amino group. The detach-
ment can proceed at the end of the polymer chains, and finally
all of the polymer main-chains are fragmented. The auto-degrada-
tion systems were used in biotechnology such for labelling of the
proteins.33 Therefore, the toxicity of our polymers could be the
similar level to the previous materials. Moreover, by employing
the auto-degradable polymer, the quantum yield of photo-reaction
can be amplified, leading to the suppression of the amount of the
harmful byproducts such as nitroso species. It is proposed that
the polymer element forms the domain structures in the nanoscale
in the hybrids.40 The loaded hydrophobic molecules tend to be dis-
tributed in the polymer-rich domains.40 Therefore, after the frag-
mentation of the polymer main-chains, it is assumed that the
encapsulated ability of the hybrid materials should drastically
decreased. As a result, the hydrophobic encapsulated molecules
can be released. In this study, the two kinds of fluorescent dyes
are loaded into the hybrids to quantitatively analyze the amount
of the released molecules after the photo irradiation.
The synthesis of the monomer and polymer P1 was performed
by employing our previous report as outlined in Scheme 2.33 To
improve the solubility, the TBS groups were introduced into P1
at the side chains. In the presence of dibutyltin dilaurate (DTDL)
as a catalyst and 4,5-dimethoxy-2-nitrobenzyl alcohol as an end
cap, the polymerization was carried out. Although we also tried
polymerization reaction in the absence of the end-capping, the
products with smaller molecular weights were obtained. It is pre-
sumed that the polymer without the end capping could be instable
due to the auto-degradable process. The number-average molecu-
lar weight (Mn) of the product was estimated as 16,000 by gel per-
meation chromatography (GPC, polystyrene standards, DMF
eluent). The synthesized polymer P1 showed good solubility in
organic solvents such as DMF and DMSO. After reprecipitation in
methanol, P1 was collected. From 1H NMR analysis, it was con-
firmed that P1 had the desired chemical structure as we designed.
To evaluate the photo-cleavable reactivity of the end caps in
the polymer, the time-course of the spectrum change in UV–vis
absorption was examined with variable time of UV irradiation
(Fig. 1). By increasing UV irradiation time, the absorption band
around 350 nm assigned as the nitro group decreased.33 In addi-
tion, the absorption band around 400 nm increased. According
to the previous reports, these data mean the generation of the
2.2. Compound 2
Compound 133 (2.5 g, 5.39 mmol) was suspended in a 31 mL of
the mixture of THF/satd NaHCO3aq/water (ratio 2:2:1). Phenyl
chlorocarbonate (685 lL, 852 mg, 5.44 mmol) was added dropwise
over 5 min. After stirring for 1 h, the reaction was monitored by
TLC (EtOAc/hexane = 1:4). Methoxycyclopentane was added, and
the organic phase was washed with satd NaHCO3aq and brine.
The solvent was removed under reduced pressure, and the crude
product was purified by column chromatography on silica gel
(EtOAc/hexane = 1:4). The crude product was recrystallized with
toluene/heptane. Compound 2 was obtained as a white powder
(2.33 g, 74%). 1H NMR (DMSO-d6): d 9.40 (s, 0.3H), 9.30 (s, 0.7H),
7.47–7.7.38 (m, 3H), 7.17–7.12 (m, 2H), 6.86–6.73 (m, 4H),
6.42–6.36 (m, 2H), 5.23 (q, J = 6.0 Hz, 1H), 4.50 (s, 2H), 4.37
(s, 4H), 0.912 (s, 18H), 0.097 (s, 12H). HRMS (ESI): m/z calcd for
C
32H49NO5Si2+NH+4 (M+NH4+): 601.3488. Found: 601.3487.
2.3. P1
Compound 2 (1.0 g, 1.71 mmol), 4,5-dimethoxy-2-nitrobenzyl
alcohol (73 mg, 0.34 mmol) and DBTL (5 mol %) were dissolved in
dry DMSO (3.43 mL) and heated at 115 °C under argon atmosphere.
The solution was stirred for 45 min. After cooling to room temper-
ature, the polymer was precipitated from methanol, filtered and
dried under reduced pressure for a few hours. The polymer P1
was obtained as
a
white powder (868 mg, Mn = 16000,
Mw = 20000, 95%). This polymer is soluble in THF. 1H NMR (THF-
d8): d 10.7 (s), 7.51 (br) 7.41 (s), 6.81 (br), 6.22 (br), 5.05 (br),
4.49 (d), 4.28 (br), 0.86 (s), 0.07 (s).
2.4. Preparation of hybrids films
Hybrid films were prepared by the acid-catalyzed sol–gel reac-
tion of methyltetramethyl orthosilicate (MeTMOS) using 0.1 M HCl
aqueous solution. Polymer P1 was dissolved in DMF (200 mg/L),
HCl, and MeTMOS was added. After stirring for 5 min, the reaction
solution was poured into a polypropylene vessel, and then heated
at 60 °C for 2 days. The transparent hybrid films were obtained.
2.5. Preparation of hybrids containing dyes
Hybrids films containing boron dipyrromethene (BODIPY) and
fluorescein dyes were prepared by the acid-catalyzed sol–gel reac-
tion of tetramethyl orthosilicate (TMOS) using 0.1 M HCl aqueous
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H. Okada et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
3
R
R
H
O2N
O
N
H
N
O
h
ν
O
O
R
O
R
MeO
OMe
OTBS
P1
R =
R
R
R
R
CHO
OMe
ON
H2N
H
N
O
CO2
O
+
+
O
MeO
Release
R
R
H2N
O
R
Auto
degradation
CO2
HN
+
Scheme 1. Chemical structure of materials and proposed mechanism for molecular release triggered by light-driven auto-degradation of polymers in hybrid materials.
TBSO
TBSO
a
H2N
O
O
HN
OH
OH
TBSO
TBSO
1
2
TBSO
TBSO
b
H
N
H
N
O2N
O
O
O
OH
n
O
TBSO
OMe
TBSO
MeO
P1
Scheme 2. Synthesis of P1. Reagents and conditions: (a) Phenyl chloroformate, THF/satdÁNaHCO3aq/water, rt 1 h, 74%; (b) dibutyltin dilaurate, 4,5-dimethoxy-2-nitrobenzyl
alcohol, DMSO, 115 °C, 40 min. Mw = 2.0 Â 104, Mn = 1.6 Â 104. TBS = tert-butyldimethylsilyl.
Figure 1. Time-courses of the changes in UV–vis spectra of P1 solution (0.2 g/L) in DMF (a) with and (b) without UV irradiation.
nitroso compound which is the degradation product from
o-nitrobenzyl ether in the photoreaction.33 Within 20 h, the
starting material was completely consumed. Without UV
irradiation, the spectrum changes were hardly observed. From
these results, it is indicated that the synthesized can be acti-
vated by UV irradiation.
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H. Okada et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
aggregation of the dyes (Fig. 3). In previous reports, it is known
that BODIPY can readily form the aggregation, resulting in the color
changes to orange, while such unfavorable changes were less
observed.41 From the microscopic observation, the phase separa-
tion or cracks were hardly detected. These data indicate that the
homogeneous hybrids can be prepared. In the presence of the dyes,
transparent hybrids can be also obtained. Although we also applied
other alkoxysilanes such as phenyl-, methyl-, and octyltrimethoxy-
silanes, in the sol–gel reaction, the fragile fragments were
obtained. Consequently, it was found that the transparent colored
materials can be obtained only with TMOS. By using ammonium
hydroxide as a catalyst, the homogeneous hybrid was not obtained.
It is assumed that P1 could be decomposed under the basic
condition.
Figure 2. GPC profiles of P1 before (gray line) and after (black line) the UV
irradiation.
The photo-degradation was monitored by GPC (polystyrene
standards, DMF eluent). After UV irradiation for 24 h, the Mn of
the polymer was significantly reduced from 16,000 to 2000
(Fig. 2). The Mn of the monomer was determined as 2500 under
the same solvent condition. This result directly indicates that deg-
radation of the polymer should occur after UV irradiation. In our
previous report, it was observed that the molecular release at the
para position toward the amino group can occur immediately just
after removing the end-cap group. The degradation rate of the
main-chain was much faster than that of the photo-cleavage of
the end cap. Thereby, the reaction rate was not determined.
The hybrid materials were prepared via the acid-catalyzed sol–
gel method.41 The reaction mixture containing 0.1 M HCl aq, TMOS,
and the synthesized polymer in DMF was heated with an oven at
60 °C for 5 days. The transparent hybrids were obtained without
Figure 4. UV–vis spectra of hybrid film with UV irradiation.
Figure 3. Appearances (top) and SEM observations before (middle) and after (bottom) the UV irradiation at 365 nm. The scale bars represent 10 lm.
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H. Okada et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
5
Figure 5. Amount of released (a) BODIPY in THF and (b) fluorescein in water. The plots were obtained from the averages of three data sets. The error bars mean standard
deviation.
To evaluate the photo reactivity of the polymer in the hybrid
film, the time-course of the spectrum change in UV–vis absorption
of the hybrid film was monitored with variable time of UV irradi-
ation (Fig. 4). Initially, it was observed that the absorption spectra
of the hybrids showed good agreement with that of P1 in the solu-
tion. These data mean that P1 can be incorporated into the hybrid
without degradation. Corresponded to the results in the solution,
the absorption band around 350 nm and 400 nm attributed to
the generation of the nitroso compounds increased by increasing
UV irradiation time.31 These data mean the end capping of the
polymer main-chain was cleaved by the light irradiation. Consider-
ing the result from the degradation behavior of the polymer in the
solution, the subsequent main-chain degradation could occur in
the hybrids. Without the UV irradiation, the significant changes
were hardly detected at least after the storage for one week in
the air. It is suggested that only the UV irradiation could induce
the auto-degradation of the polymer main-chains.
indicate that the synthesized hybrids containing the auto-degrad-
able polymer can release the loaded guest molecules triggered by
the light irradiation. As shown in Figure S1, the emission intensi-
ties from both samples with or without UV irradiation were com-
pared. If the photodegradation occurs, the amount of the released
dyes should be apparently reduced in the UV-irradiated samples,
whereas we obtained the similar intensities from the samples with
or without UV irradiation. These data represent that the loaded
dyes were protected from the photodegradation in the hybrids.
The encapsulation by the hybrid can enhance the stability to the
encapsulated guest molecules as often observed in the hybrids or
the silica-based materials.42 The powder samples were prepared
with mechanical levigation. By using the nanoparticles, the
amount of the released dyes could be improved.
4. Conclusion
Finally, the photo-triggered release of the guest molecules from
the hybrids was performed (Fig. 5a). We prepared the two kinds of
the dye-loaded hybrids containing the auto-degradable polymers.
The changes in the amount of the released dyes in the media were
plotted. Initially, boron-dipyrromethene (BODIPY) was introduced
into the hybrid, and the releasing behavior was evaluated. BODIPY
derivatives are well known as a fluorophore with suitable optical
properties as a bioprobe such as high emission quantum yield,
large absorption, and high stability under biological conditions.
However, because of extremely poor solubility, the aggregation
of BODIPY molecules readily proceeds in the polar solvents, result-
ing in the spoil of optical properties. With the sol–gel reaction as
shown above in the presence of a BODIPY dye, the homogeneous
material can be obtained. The UV light (254 nm) was irradiated
for 2 days in open air. The sample was levigated, and 10 mg of
the powder was immersed into THF. The amount of dyes released
into the solution was estimated from the emission intensity of the
dye from the filtrate. From the sample without UV irradiation, the
released BODIPY was hardly detected. On the other hand, the BOD-
IPY dye was observed from the sample with UV irradiation. These
data clearly indicate that BODIPY can be released from the hybrids
triggered by the light irradiation. In water phase, the molecular
release slightly occurred. It is likely that BODIPY should be
adsorbed at the surface of the hybrid because of the strong
hydrophobicity.42
The photo-triggered molecular release from the organic–inor-
ganic polymer hybrids is demonstrated in this manuscript. The sil-
ica-based dye-loaded hybrids containing these polymers were
prepared. It was shown that the molecular release of the loaded
dyes occurred in various media triggered by the UV irradiation.
Moreover, both of hydrophobic and hydrophilic dyes can be used
in this system. It is proposed that hybrid-based molecular release
possesses the advantages derived from both organic and inorganic
elements: By altering the type of polymers, the release rate and the
amount of the loaded dye molecules could be controlled. As shown
in this study, the stability of the loaded dyes can be enhanced
owing to the inorganic element. Thus, the hybrid-based molecular
carrier for drug release is promised to be versatile for various bio-
logical events and conditions.
Acknowledgments
This study was partially supported by Nippon Sheet Glass Foun-
dation for Materials Science and Engineering (for K.T.) and by a
Grant-in-Aid for Scientific Research on Innovative Areas ‘New Poly-
meric Materials Based on Element-Blocks (No. 2401)’ (25102521)
of The Ministry of Education, Culture, Sports, Science, and Technol-
ogy, Japan.
Supplementary data
By using fluorescein as a fluorophore, the similar experiment
was performed (Fig. 5b). The UV light was irradiated to the fluores-
cein-loaded hybrid for 2 days at room temperature, and the levi-
gated sample was soaked into water. The emission intensity in
the filtrate was evaluated with a fluorescence spectroscopy. By
UV irradiation, the molecular release from the hybrids was obvi-
ously induced. Fluorescein is more water-soluble than BODIPY.
Therefore, the slight release was observed from the sample with-
out UV irradiation. These data including the results with BODIPY
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2014.04.034.
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