A photocleavable low molecular weight hydrogel for light-triggered drug delivery

Article abstract of DOI:10.1016/j.cclet.2018.06.009

A photocleavable low-molecular-weight hydrogelator (LMWG) was synthesized based on coumarin derivative. ¹H NMR and UV spectroscopy study suggested that the gelator had good gelling ability, and the driving force for the gelation were hydrogen bonding and π-π stacking. This molecular hydrogel exhibited satisfied photocleavage at C-N bond in 7-amino coumarin with the light irradiation (365 nm, 77.5 mW/cm²). The promising photo-triggered drug release of antineoplastics cytarabine hydrochloride has been obtained, due to the photocleavage motived gel-sol transition.

Full text of DOI:10.1016/j.cclet.2018.06.009

G Model
CCLET 4585 No. of Pages 4
Chinese Chemical Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
A photocleavable low molecular weight hydrogel for light-triggered
drug delivery
Qihong Liu, Hao Wang, Guotao Li, Miaochang Liu, Jinchang Ding, Xiaobo Huang,
Wenxia Gao*, Huayue Wu*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 30 April 2018
Received in revised form 31 May 2018
Accepted 6 June 2018
Available online xxx
A photocleavable low-molecular-weight hydrogelator (LMWG) was synthesized based on coumarin
derivative. H NMR and UV spectroscopy study suggested that the gelator had good gelling ability, and the
1
driving force for the gelation were hydrogen bonding and
p-p stacking. This molecular hydrogel
exhibited satisfied photocleavage at C-N bond in 7-amino coumarin with the light irradiation (365 nm,
2
7
7.5 mW/cm ). The promising photo-triggered drug release of antineoplastics cytarabine hydrochloride
Keywords:
Low-molecular-weight hydrogelator
Photocleavage
has been obtained, due to the photocleavage motived gel-sol transition.
©
2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Photo-triggered
Drug delivery
Light-responsive controlled drug delivery system has exhibited
more and more important in cancer diagnosis and treatment, since
light stimulus was a non-invasive trigger, which could effectively
penetrate the body's tissues and implement to control release in
fixed point at required time [1–4]. In recent years, a series of
researches have been carried out on light-sensitive drug carrier
materials [5]. According to the difference in response to light, the
light response chromophores can be divided into the photo-
isomerisable materials represented by azobenzene (Azo) and
stilbenes [6,7], photoinduced ring opening and closing materials
represented by dithienylethenes and spiropyrans [8,9], photo-
dimerisation and photopolymerisation represented by coumarin
and anthracenes [10,11], photocleavage represented by pyrene and
nitrobenzyl [12,13].
cleaved upon ultraviolet [18]. There was also another type of light
response of coumarin derivative upon photoinduced bond
breaking, a few cases of 7-amino-4-hydroxymethyl coumarin
cleaved at the 4-methyl end were reported [19–22], such as Zhao
and coworkers reported a 7-amino-4-hydroxymethyl coumarin
grafted poly(glutamic acid) based nanoparticles, which could
release drug using light-responsive bond broken to destroy the
nanoparticles [23,24]. Zink and coworkers adopted 7-amino-4-
hydroxymethyl coumarin on the surface of mesoporous silicon
dioxide, and used photolysis of coumarin as a photocontrol switch
to control the drug release from mesoporous silica [25]. We also
reported an efficient nanocarrier by bonding 7-amino-4-hydrox-
ymethyl coumarin derivatives on the surface of the gold nano-
particles to realize photo-responsive fracture at the 4-methyl end
of coumarin [26].
In this study, we found another new photosensitive broken site
of 7-amino coumarin derivative, and fabricated a novel photo-
responsive molecular hydrogel based on this new photosensitive
site. This gel went through a photocleavage of C-N bond in 7-amino
coumarin upon the irradiation with UV light. The photo-controlled
drug release of this molecular hydrogel has been investigated.
The synthetic route of gelator was presented in Scheme 1, the
characterization of the gelator was showed in Figs. S1-S27
(Supporting information). The designed gelator had good gelation
by immobilizing the solvents in the three-dimensional network.
The critical gelation concentration (CGC) of the gelator was 2.7 mg/
Light sensitive materials based on coumarin derivatives have
been reported mainly based on dimerisation of the coumarin
molecule upon irradiation with light >300 nm [14,15]. A small
number of photo-responsive low molecular weight hydrogels
(
LMWGs) based on coumarin have been reported [16]. Parquette
and co-workers designed a coumarin dipeptide hydrogelator,
photodimerisation of the gelator was carried out exposing to 365
nm light with a dark yellow precipitate forming in the beginning,
and insoluble precipitate becoming after 7 days under the 365 nm
light [17]. Almutairi and co-workers designed a hydrogel based on
the photocage bromohydroxycoumarin which was efficiently
2
mL in PEG200:H O = 1:2. SEM image of the gel indicated that the
gel consisted of spiral-shaped fibers (30-60 nm wide), and these
nanofibers further assembled into three-dimensional network
*
Corresponding authors.
E-mail address: wenxiag@wzu.edu.cn (W. Gao).
https://doi.org/10.1016/j.cclet.2018.06.009
001-8417/© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
1
Please cite this article in press as: Q. Liu, et al., A photocleavable low molecular weight hydrogel for light-triggered drug delivery, Chin. Chem.
Lett. (2018), https://doi.org/10.1016/j.cclet.2018.06.009

G Model
CCLET 4585 No. of Pages 4
2
Q. Liu et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
Scheme 1. The synthesis of gelator (compound 7).
Fig. 1. (a) gelator, (b) self-assembly of gelator, (c) photo and SEM images of gel, (d) photo and SEM images of gel, upon laser irradiation, (e, f) 1H NMR spectra of gel with
different concentration.
1
(
Fig. 1c). H NMR spectra showed the gradual high-field shift of
respectively, with increasing concentration from 1.0 mg/mL (sol)
to 14.7 mg/mL (gel), for the presence of stacking. The p
conjugated moieties of the molecular structure containing
coumarin and phenylalanine, which strengthened intermolecular
protons upon increasing the concentration of gelator (Figs. 1e and
f). The protons at 7.73 ppm, 7.61 ppm, 7.50 ppm, 7.41 ppm, 7.35 ppm
and 6.52 ppm attributed to benzene units shifted downfield to 7.77
ppm, 7.64 ppm, 7.53 ppm, 7.44 ppm, 7.38 ppm and 6.55 ppm,
p
-p
p-p stacking to self-assemble into network to immobilize a large
Please cite this article in press as: Q. Liu, et al., A photocleavable low molecular weight hydrogel for light-triggered drug delivery, Chin. Chem.
Lett. (2018), https://doi.org/10.1016/j.cclet.2018.06.009

G Model
CCLET 4585 No. of Pages 4
Q. Liu et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
3
volume of solvent in the gel [27]. The
p
-
p
stacking interaction
hydrophobic. This decrease in solubility can lead to destruction of
the gel or a decrease in the rheological properties due to the gel
network being disruption of the gel network [31]. Different from
traditional photodimerisation of coumarin gel, the light response
of this gel was mainly achieved by the photocleavage. After
exposing to light, this gel was photodegraded into sol. The sol was
tested by high performance liquid chromatography (HPLC). Two
between gelators was also characterized by UV spectra (Fig. S28 in
Supporting information), the red-shift occurred as the concentra-
tion increasing [28]. Moreover, the cleavage peaks of hydrogen at
positions 3, 4, 22, 23, 24 on the aromatic ring disappeared, as the
sol-gel transition. The protons at 8.15 ppm and 8.40 ppm attributed
to amino in peptide bonds also shifted downfield with increasing
gelator concentration for the intermolecular hydrogen bond. The
formation of hydrogen bonds between these peptide bonds might
be responsible for the formation of spiral-shaped fibers in the gel
peaks with the retention time R
t
= 3.4 min and R
t
= 8.3 min were
= 3.4 min
found (Fig. 2D). The corresponding compound with R
t
1
was detected by H NMR as coumarin, as show in Fig. S29 in
Supporting information. The results demonstrated the gelator was
photocleaved gradually into the coumarin in the exposure to light.
It was also found that gelator in solution was more sensitive to light
than that in gel (Fig. 2E), more coumarin was cleaved from the
gelator in solution. The photocleavage speed of gel was much slow,
this might owe to the enhanced molecular interaction in gel state,
which weakened the degradation speed of gelator exposing to
light.
(Fig.1c). These results implied that the self-assembly of gelator was
driven by hydrogen bond as well as
gelation [29].
p-p interaction during the
The photocleavable property of the gel was investigated as
shown in Fig. 2. The gelator was responsive to 365 nm irradiation,
but stable under 420 nm, 630 nm and natural light, as shown in
Fig. 2A(a). The gel gradually transformed into sol under UV
2
irradiation (365 nm, 77.5 mW/cm ), and the sol gradually turned
yellow (Fig. 2A(c)), the ultraviolet and fluorescence intensity
gradually weakened (Fig. 2B and C). The photosensitive material
based on coumarin has been reported to realize the light response
usually through photoinduced dimerization [30]. Dimerisation of
the gelator molecule often led to the molecules being less soluble
due to the molecule doubling in size and so becoming more
In order to evaluate the photo-sensitive controlled release,
cytarabine hydrochloride was selected as the model drug, a
chemotherapy medication used to treat acute myeloid leukemia,
acute lymphocytic leukemia, and chronic myelogenous leukemia
[32]. Since cytarabine hydrochloride is less sensitive to light, which
can avoid the effect of light on drug during evaluating the photo-
Fig. 2. (A) Images of gelator in solution and gel with or without exposure to laser irradiation: (a) gelator in solution with exposure to different laser irradiation (1, in dark; 2,
with natural light; 3, with 630 nm irradiation; 4, with 420 nm irradiation; 5, with 365 nm irradiation for 10 min; 6, with 365 nm irradiation for 20 min), (b) gel under natural
light for different time, (c) gel with laser irradiation for different time. (B) UV spectra and (C) fluorescence spectra of gel during light-exposure with different time, insert image
0 0
is the fluorescent intensity ration I/I , I = fluorescent intensity of gelator with different irradiation time, I = fluorescent intensity of gelator. (D) HPLC spectra of gel after the
2
laser irradiation (365 nm, 77.5 mW/cm ) with different time. (E) the concentration of coumarin photocleaved from the gelator in gel or in solution during exposing to the light.
Please cite this article in press as: Q. Liu, et al., A photocleavable low molecular weight hydrogel for light-triggered drug delivery, Chin. Chem.
Lett. (2018), https://doi.org/10.1016/j.cclet.2018.06.009

G Model
CCLET 4585 No. of Pages 4
4
Q. Liu et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
2
Fig. 3. (A) the released profile of cytarabine hydrochloride-loaded gel in PBS (7.4) with or without laser irradiation (365 nm, 77.5 mW/cm ). Means + SD (n = 3). (B) the release
profile of cytarabine hydrochloride-loaded gel in different media. All the drug-loaded gels were prepared by adding 5.0 mg gelator and 1.0 mg cytarabine hydrochloride in 3
mL PBS (pH 7.4).
sensitive controlled release. The cytarabine hydrochloride was
often given by intravenous injection, but it quickly disappeared
and eliminated from the blood, and T1/2 was only 3-15 min. There
was a liposomal formulation for cytarabine reported to outcomes
the quick elimination [33]. In this study, the molecular hydrogel
was used to photo-triggered delivery for cytarabine. In vitro release
of cytarabine from drug-loaded hydrogel was carried out, as shown
in Fig. 3. With the comparison of cytarabine releasing with and
without laser irradiation (Fig. 3A), the concentration of cytarabine
Acknowledgment
The authors thank for the financial support of National Natural
Science Foundation of China (Nos. 21672164, 21372177)
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2018.06.009.
increased from 39.41
mg/mL to 104.27 mg/mL with an increment of
6
4.86 g/mL under 40 min laser irradiation at the time point of 60
m
References
min, and nearly no increase of cytarabine with no laser irradiation
at the same time. It was clear that laser could accelerate the
photocleavage of gelator, and the cleavage of the C-N bond could
further destroy the architecture of gel and accelerated the release
of cytarabine. The release of drug-loaded gel in phosphate buffer
with different pH values was also investigated, as shown in Fig. 3B.
The hydrogel exhibited promising controlled release behavior with
sustained release of cytarabine in buffer solutions. Few cytarabine
was released from the gel under natural light than that with laser
irradiation. Upon laser irradiation, few cytarabine was released
from the gel in physiological environment (pH 7.4), and the release
rate increased in PBS with acidic or alkaline environment (pH 8.5).
This drug-loaded hydrogels with stability and sustaining drug
release could be used intratumoral injection or other target
injection, which is a research focus in the tumor treatment now.
In this study, a new coumarin derivative based molecular
hydrogel has been fabiricated, which exhibited satisfied photo-
sensitivity. This gel went through a photocleavage of C-N bond in 7-
amino coumarin upon the UV light irradiation based on a new
photosensitive broken site of 7-amino coumarin derivative. The
designed gelator had good gelation by immobilizing the solvents in
the three-dimensional network. The critical gelation concentration
[
[
[
1] W.C. Liao,Y.S. Sohn, R. Nechushtai, etal., J. Am. Chem.Soc.138(2016)8936–8945.
2] S. Theis, A. Iturmendi, C. Gorsche, et al., Angew. Chem. Int. Ed. 56 (2017) 1–5.
3] S.O. Poelma, S.S. Oh, S. Helmy, et al., Chem. Commun. 52 (2016) 10525–10528.
[4] P. Xiao, J. Zhang, J. Zhao, M.H. Stenzel, Prog, Polym. Sci. 74 (2017) 1–33.
[
[
[
5] H. Li, X. Yang, Z. Zhou, J. Control Release 261 (2017) 126–137.
6] C. Lin, S. Maisonneuve, R. Metivier, J. Xie, Chem. -Eur. J. 23 (2017) 14996–15001.
7] Y. Zhou, S. Yang, J. Li, et al., Dalton Trans. 45 (2016) 18308–18312.
[8] Y. Kang, X. Tang, H. Yu, et al., Chem. Sci. 8 (2017) 8357–8361.
[9] S. Son, E. Shin, B.S. Kim, Biomacromolecules 15 (2014) 628–634.
10] H.M. Lin, W.K. Wang, P.A. Hsiung, S.G. Shyu, Acta Biomater. 6 (2010) 3256–3263.
11] T.K. Claus, S. Telitel, A. Welle, et al., Chem. Commun. 53 (2017) 1599–1602.
[12] J.E. Lee, E. Ahn, J.M. Bak, et al., Polymer 55 (2014) 1436–1442.
[13] T. Nishimura, M. Takara, S. Mukai, et al., Chem. Commun. 52 (2016) 1222–1225.
14] P. Wei, H. Wang, K. Jie, F. Huang, Chem. Commun. 53 (2017) 1688–1691.
15] H. He, M. Feng, Q. Chen, X. Zhang, H. Zhan, Angew. Chem. Int. Ed. 55 (2016)
[
[
[
[
9
36–940.
[16] E.R. Draper, T.O. McDonald, D.J. Adams, Chem.Commun. 51 (2015)12827–12830.
[
17] S.H. Kim, Y. Sun, J.A. Kaplan, M.W. Grinstaff, J.R. Parquette, New J. Chem. 39
2015) 3225–3228.
18] C. de Gracia Lux, J. Lux, G. Collet, et al., Biomacromolecules 16 (2015) 3286–3296.
(
[
[19] N. Fomina, C.L. McFearin, M. Sermsakdi, J.M. Morachis, A. Almutairi,
Macromolecules 44 (2011) 8590–8597.
[
[
20] J. Cao, S. Huang, Y. Chen, et al., Biomaterials 34 (2013) 6272–6283.
21] L.L. Fedoryshin, A.J. Tavares, E. Petryayeva, S. Doughan, U.J. Krull, ACS Appl,
Mater. Interfaces 6 (2014) 13600–13606.
[
[
[
22] G. Yu, W. Yu, Z. Mao, C. Gao, F. Huang, Small 11 (2015) 919–925.
23] S. Kumar, J.F. Allard, D. Morris, et al., J. Mater. Chem. 22 (2012) 7252–7257.
24] Q. Lin, C. Bao, Y. Yang, et al., Adv. Mater. 25 (2013) 1981–1986.
[25] T.M. Guardado-Alvarez, L.S. Devi, et al., J. Am, Chem. Soc. 135 (2013) 14000–14003.
[26] Y. Liang, W. Gao, X. Peng, et al., Biomaterials 100 (2016) 76–90.
27] T.B. Wei, J.F. Chen, X.B. Cheng, et al., Polym. Chem. 8 (2017) 2005–2009.
28] H. Fang, H. Gao, T. Wang, et al., Dyes and Pigments 147 (2017) 190–198.
29] A. Dawn, H. Kumari, Chem. -Eur. J. 23 (2017) 1–16.
[30] Y.F. Han, G.X. Jin, C.G. Daniliuc, F.E. Hahn, Angew. Chem. Int. Ed. 54 (2015)
958–4962.
31] Z. Zheng, J. Hu, H. Wang, et al., ACS Appl. Mater. Interfaces
4511–24517.
[32] A.D. Tullio, K. Rouault-Pierre, A. Abarrategi, et al., Nat. Commun. (2017) 1679.
33] S. Kim, S. Khatibi, S.B. Howell, et al., Cancer Res. 53 (1993) 1596.
was 2.7 mg/mL in PEG200:H
2
O = 1:2. The cytarabine hydrochloride
was selected as the model drug to evaluate the photo-triggered
drug delivery. The hydrogel exhibited promising controlled release
behavior with laser to accelerate the photocleavage of C-N bond of
gelator, which could destroy the architecture of gel and accelerated
the release of cytarabine. This drug-loaded hydrogels could be used
intratumoral injection or other target injection with a non-invasive
light stimulus triggered release, which is a research focus in the
tumor treatment now.
[
[
[
4
[
9 (2017)
2
[
Please cite this article in press as: Q. Liu, et al., A photocleavable low molecular weight hydrogel for light-triggered drug delivery, Chin. Chem.
Lett. (2018), https://doi.org/10.1016/j.cclet.2018.06.009