Photo-controllable molecular hydrogels for drug delivery

Article abstract of DOI:10.1166/jnn.2014.8275

A photocleavable nitrobenzyl ester group was introduced in the backbone of self-assembling peptides using standard Fmoc-peptide systhesis. The nitrobenzyl ester group could be used as a cleavable linker to connect a gelator and a hydrophilic group. Photo-irradiation would lead to the generation of the molecular gelator and the formation of a molecular hydrogel. The nitrobenzyl ester group could also be used as one part of hydrophobic capping group for short peptides to produce molecular hydrogelators. In this case, photo-irradiation would lead to the release of hydrophobic anti-imflammatory drug of Naproxen and the gel-sol phase transition. The application of photocleavable group in molecular self-assembly would lead to photo-controllable self-assembly materials for controlled drug release, tissue engineering, and regenerative medicine. Copyright

Full text of DOI:10.1166/jnn.2014.8275

Article
Journal of
Nanoscience and Nanotechnology
Vol. 14, 4837–4842, 2014
Copyright © 2014 American Scientific Publishers
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Printed in the United States of America
Photo-Controllable Molecular Hydrogels for Drug Delivery
Hanxia Liu1ꢀ2, Zhijian Song1, and Xuemei Chen1ꢀ∗
1School of Chemical and Materials Engineering, Hubei Institute of Technology, Huangshi 435003, P. R. China
2School of Chemical and Environmental Engineering, Hubei University of Technology, Wuhan 430068, China
A photocleavable nitrobenzyl ester group was introduced in the backbone of self-assembling pep-
tides using standard Fmoc-peptide systhesis. The nitrobenzyl ester group could be used as a
cleavable linker to connect a gelator and a hydrophilic group. Photo-irradiation would lead to the
generation of the molecular gelator and the formation of a molecular hydrogel. The nitrobenzyl ester
group could also be used as one part of hydrophobic capping group for short peptides to produce
molecular hydrogelators. In this case, photo-irradiation would lead to the release of hydrophobic
anti-imflammatory drug of Naproxen and the gel-sol phase transition. The application of photocleav-
able group in molecular self-assembly would lead to photo-controllable self-assembly materials for
controlled drug release, tissue engineering, and regenerative medicine.
Keywords: Self-Assembly, Photo-Cleavable Linker, Drug Release, Hydrogel.
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1. INTRODUCTION
cleavable linker to connect a gelator and a hydrophilic
Copyright: American Sgcrioeunptifitco Pguebnleisrahteersa precursor of gelator with good
IP: 206.125.156.201 On: Fri, 27 Nov 2015 16:52:30
Molecular hydrogels are formed by small molecules with
fine-tuned balance of hydrophobicity and hydrophilicity.1–5
They have been applied in fields of controlled drug
release,6–10 tissue engineering,11–16 material science,17–22
etc. In order to form a molecular hydrogel, external stim-
uli such as pH and temperature adjustment and addition
of enzyme, salts, and other reactive agents are needed.23–29
These external stimuli can induce the self-assembly of
small molecules or produce molecular hydrogelators from
their precursors. Recently, biocompatible stimuli used
for molecular hydrogelations attract extensive research
interests. For example, Nilssion and Yang groups used
glutathione (GSH) to trigger disulfide bond reduction,
leading to the generation of molecular hydrogelators and
hydrogelations.23–29 Several groups have used salts or spe-
cific metal ions such as Zn2+, Ca2+, and K+ to trigger
the folding of peptides and hydrogelations.30–32 The hydro-
gels formed by biocompatible external stimuli have shown
promising applications for cell culture, controlled drug
release, and detection of heavy metals.33–35
solubility in aqueous solution. Therefore, photo-irradiation
can lead to the release of the gelator and the formation
of gel. Many aromatic capped short peptides have been
demonstrated as efficient hydrogelators.38–43 Photocleav-
able group, in combine with a hydrophobic drug molecule,
may also be used as a hydrophobic capping group for
short peptides to produce short peptide-based hydroge-
lators. In this case, the resulting hydrogels can release
drug molecules upon photo-irradiation. In this study,
we demonstrate that a photocleavable group, nitrobenzyl
ester group, can be used to control the self-assembly of
small molecules and for controlled release of an anti-
inflammatory drug of Naproxen.
2. EXPERIMENTAL DETAILS
2.1. General Methods and Chemicals
Fmoc-amino acids were obtained from GL Biochem
(Shanghai, China). Other reagents were purchased from
Aladdin Chemistry CO. Ltd., Solvents were obtained
locally. Commercially available reagents were used with-
out further purification. All other chemicals were reagent
grade or better. Nanopure water (18.2 ꢁ) was used. 4-(4-
(1-hydroxyethyl)-2-methoxy-5-nitrophenoxy)butanoic acid
was synthesized according to the Refs. [36, 44].
Several groups have developed photo-responsive molec-
ular hydrogels with potential promising applications. Pho-
tocleavable groups have been widely used to spatially and
temporally control the bioactivity in hydrogels.36ꢀ37 We
think that photocleavable group may also be used as a
The synthesized compounds were characterized using
∗Author to whom correspondence should be addressed.
1H NMR (Bruker ARX 300). ESI-MS spectrometric
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doi:10.1166/jnn.2014.8275
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Photo-Controllable Molecular Hydrogels for Drug Delivery
Liu et al.
analyses were performed at the Thermo Finnigan LCQ AD
System. HPLC was conducted at Waters semi-preparation
HPLC system using a C18 RP column with MeOH (0.05%
of TFA) and water (0.05% of TFA) as the eluents. TEM
images were done on a Tecnai G2 F20 system, operat-
ing at 150 kV, TEM samples were prepared as following:
a carbon-coated copper grid (Zhongjingkeyi Technology
Co. Ltd., Beijing, China) was vertically dipped into the
hydrogel for 5 sec and then placed in a desicator overnight
before the TEM measurement. LC-MS was recorded on
the LCMS-20AD (Shimadzu) system, and rheology was
performed on an AR 1500ex (TA instrument) system using
a parallel plates (40 mm) at the gap of 400 ꢂm. The photo-
irradiation was conducted in a UV crosslinker (SelectTM
Series UV Crosslinkers, Spectroline).
M+ = 1646ꢅ6, obsvd. ꢆM +1ꢃ+ = 1647ꢅ6. HR-MS: ꢆM +
1ꢃ+ = 1647ꢅ5910.
1
N-GFFY-PL-E: H NMR (300 MHz, DMSO-d6ꢃꢄ9ꢅ31
(s, 1 H), 8.35–8.57 (m, 1 H), 8.10–8.26 (m, 3 H),
8.00–8.08 (d, J = 8ꢅ03, 1 H), 7.80–7.98 (m, 1 H),
7.65–7.78 (t, 3 H), 7.49–7.59 (d, 1 H), 7.36–7.48 (m,
2 H), 6.93–7.35 (m, 14 H),6.55–6.75 (m, 1 H), 4.35–
4.60 (m, 3 H), 4.13–4.29 (m, 1 H), 3.67–4.09 (m, 10 H),
2.71–3.07 (m, 6 H), 2.20–2.33 (m, 3 H), 1.85–2.03 (m,
3 H), 1.70–1.83 (m, 1 H), 1.49–1.69 (m, 4 H), 1.16–1.46
(m, 6 H), MS: calc. M+ = 1152ꢅ5, obsvd. ꢆM + 1ꢃ+
=
1153ꢅ5. HR-MS: ꢆM +1ꢃ+ = 1153ꢅ4377.
2.4. Hydrogel Preparation
Photo-induced gel: The PBS solution of N-GFFY-PL-E
was put in the UV crosslinker and the gel would form
after 5 h. GSH-triggered gel: To a PBS solution of N-PL-
GFFYE-ss-EE, 2 equiv. of GSH was added. The gel would
form within 10 minutes. Final concentration of precursors
of gelators in solutions was 1.0 wt%.
2.2. Peptide Synthesis
The compounds were synthesized by solid phase peptide
synthesis (SPPS) using 2-chlorotrityl chloride resin. The
corresponding N-Fmoc protected amino acids with side
chains properly protected, Fmoc-succinated cystamine,
2.5. Photo-Irradiation for Controlled Drug Release
To the GSH-triggered gel (0.4 mL), 1 mL of PBS buffer
was added. 0.9 mL of upper PBS buffer was taken
out at every half an hour under UV irradiation or in
dark for LCMS determination of the releasing profile.
and
4-(4-(1-hydroxyethyl)-2-methoxy-5-nitrophenoxy)
butanoic acid were used for SPPS. The first amino acid
was loaded on the resin at the C-terminal with the loading
efficiency about 0.6 mmol/g. 20% piperidine in anhy-
drous N,Nꢀ-dimethylformamide (DMF) was used during
0.9 mL of fresh PBS buffer was added after that. The
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deprotection of Fmoc group. The next Fmoc-protected
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UV irradiation experiments were conducted in an UV
Copyright: American Scientific Publishers
amino acid (3 equiv.) was then coupled to the free
amino group using O-(Benzotriazol-1-yl)-N,N,N ,N -
ꢀ
ꢀ
crosslinker (UL-1000 model) with a wavelength range of
254–365 nm.
tetramethyluroniumhexafluorophosphate (HBTU, 1 equiv.
to Fmoc-AA) as the coupling reagent. The growth of
the peptide chain was according to the established Fmoc
SPPS protocol. After the last coupling step, excessive
reagents were removed by a single DMF wash for 5
minutes (5 mL per gram of resin), followed by five steps
of washing using DCM for 1 min (5 mL per gram of
resin). The peptide derivative was cleaved using 92.5% of
trifluoroacetic acid with 2.5% of TMS, 2.5% of phenol,
and 2.5% of H2O for 20 minutes. 20 mL per gram of
resin of ice-cold diethylether was then added to cleavage
reagent. The resulting precipitate was filtrated and washed
by ice-cold diethylether. The resulting solid was purified
by HPLC and dried by lyophilizer.
3. RESULTS AND DISCUSSION
3.1. Nitrobenzyl Ester Group as a Photocleavable
Linker for Molecular Hydrogelation
Hydrolysable ester bond and cleavable disulfide bond
have been used to make precursors of molecular
hydrogelators.45–47 The hydrolysis of ester bond and reduc-
tion disulfide bond can then produce molecular hydroge-
lators, leading to the formation of molecular hydrogels.
Stimulated by these results, we believe that a photocleav-
able nitrobenzyl ester group can also be used as a photo-
cleavable linker (PL) to connect a gelator and a hydrophilic
group. Therefore, we designed and synthesized N-GFFY-
PL-E (Fig. 1) as the precursor of gelator with a PL.
In the design of this molecule, Naproxen (N) served as
a hydrophobic capping group to cap the short peptide of
GFFY. Many short peptide derivatives based on FF had
been demonstrated as efficient gelators,38–43 we believed
that N-GFFY could also form hydrogels. PL as the cleav-
able linker to connect N-GFFY and the hydrophilic amino
acid of glutamic acid (E). As shown in Figure 1, N-
GFFY-PL-E formed a clear solution in phosphate buffer
saline (PBS, pH = 7ꢅ4). Upon photo-irradiation, N-GFFY
could be released from the precursor, resulting in molec-
ular hydrogelation (Fig. 1). For the solution containing
2.3. Characterization of Peptides
N-PL-GFFYE-ss-EE: 1H NMR (300 MHz, DMSO-d6ꢃꢄ
9.17 (s, 1 H), 7.99–8.20 (m, 8 H), 7.87–7.96 (m,
2 H), 7.69–7.82 (m, 2 H), 7.63 (s, 1 H), 7.48 (s,1 H),
7.26–7.31 (m, 2 H), 7.09–7.23 (m, 12 H), 6.99–7.07
(d, J = 7ꢅ03 Hz, 2 H), 6.59–6.67 (d, J = 6ꢅ63 Hz, 2 H),
6.17–6.26 (m, 1 H), 4.41–4.55 (m, 3 H), 4.11–4.32 (m,
3 H), 3.93–4.06 (m, 3 H), 3.86 (s, 3 H), 3.48–3.72
(m, 4 H), 3.08 (s, 2 H), 2.86–3.03 (m, 3 H), 2.63–2.81
(m, 8 H), 2.17–2.38 (m, 13 H), 1.67–1.99 (m, 8 H), 1.46–
1.56 (m, 4 H), 1.38–1.45 (d, J = 1ꢅ42 Hz, 2 H). MS: calc.
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Liu et al.
Photo-Controllable Molecular Hydrogels for Drug Delivery
Figure 1. Optical images of a solution of N-GFFY-PL-E (1.0 wt%) and the resulting gel of N-GFFY by photo-irradiation, chemical structures, and
photo-induced conversion from N-GFFY-PL-E to N-GFFY (N and PL represents Naproxen and photocleavable linker, respectively).
1.0 wt% of N-GFFY-PL-E, the minimum time of photo-
irradiation needed for gelation was 5 h. The conversion
was the first example of molecular hydrogel with photo-
controllable drug release property.
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percentage of N-GFFY-PL-E was more than 95% in the
IP: 206.125.156.201 On: Fri, 27 Nov 2015 16:52:30
gel after 6 h photo-irradiation. The results indicated that
3.3. Mechanical Property and Morphology
Copyright: American Scientific Publishers
nitrobenzyl ester group could be used as a cleavable
linker for molecular hydrogelation, which might be used
to spatial and temporal control the formation of molecular
hydrogels.
of Nanostructures
We then went back to characterize the mechanical prop-
erty of the gels and morphology of self-assembled nano-
structures in gels. As shown in Figure 3(A), the rheology
with the mode of dynamic time sweep indicated a rapid
formation of a molecular hydrogel by adding GSH to the
PBS solution of N-PL-GFFYE-ss-EE, indicating by the Gꢀ
(elasticity) dominating Gꢀꢀ (viscosity). Both the Gꢀ and Gꢀꢀ
increased rapidly in the first 30 minutes due to the con-
version from N-PL-GFFYE-ss-EE to N-PL-GFFYE-s and
they nearly reached plateaus after about 1.5 h. Figure 3(B)
showed the dynamic frequency sweep of the gel after 2
h. the Gꢀ and Gꢀꢀ value was about 350 and 60 Pa, respec-
tively, indicating a medium strong gel sample. Since it
takes more than 5 h for the formation of a photo-induced
hydrogel from the solution of N-GFFY-PL-E and the lack
of a rheometer with UV apparatus, we were unable to
characterize the gelation process and mechanical property
of the photo-induced hydrogel. We then characterize the
morphology of nanostructures in both the GSH-triggered
gel and the photo-induced gel. GSH-triggered gel exhib-
ited small fibrils with diameter of about 40 nm that form
bundles with size of about 150–200 nm. Interestingly, the
photo-induced gel showed film structures, which was very
rarely observed in molecular hydrogels. The fibers and
films entangled with each other to form three dimensional
networks for the formation of these gels.
3.2. A Photo-Responsive Molecular Hydrogel
for Controlled Drug Release
The results in Figure 1 indicated that nitrobenzyl ester
group could be used as a cleavable linker for molecu-
lar hydrogelations. We plan to use it, in combine with
a hydrophobic drug, as aromatic capping group to cap
short peptides. Therefore, we made N-PL-GFFYE-ss-EE
as the precursor of a gelator (Fig. 2). Our group and Yang
group had used disulfide bond as the cleavable linker to
form molecular hydrogels of therapeutic agents.27ꢀ48 N-PL-
GFFYE-ss-EE could form clear solutions in PBS buffer.
As shown in Figure 2, with the addition of GSH, the
disulfide bond could be reduced by GSH and led to the
produce of N-PL-GFFYE-s and molecular hydrogelations.
Upon photo-irradiation, the hydrophobic Naproxen could
be released from the gel, leading to a gel-sol phase tran-
sition. The results indicated that nitrobenzyl ester group,
in combine with carboxylic acid containing hydropho-
bic drug molecules, could also be used as capping
groups to construct molecular hydrogelators. The resulting
hydrogels could be used for photo-controllable release of
the hydrophobic drugs. To the best of our knowledge, this
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Photo-Controllable Molecular Hydrogels for Drug Delivery
Liu et al.
Figure 2. Optical images of GSH-triggered gel and its photoresponse, chemical structures of peptides, and illustration of GSH-triggered and photo-
irradiation induced conversions (N-PL-GFFYE-ss-EE in a clear solution can be converted by GSH to N-PL-GFFYE-s that can form a gel. The resulting
gel shows a photoresponse to release Naproxen and lead to a gel-sol phase transition).
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Copyright: American Scientific Publishers
Figure 3. Rheology with the mode of (A) dynamic time sweep of a solution of N-PL-GFFYE-ss-EE (1.0 wt%) with 2 equiv. of GSH and (B) dynamic
frequency sweep of the resulting gel and transmission electron microscopy (TEM) images of (C) gel from a solution of N-GFFY-PL-E (photo-induced
gel) and (D) gel from a solution of N-PL-GFFYE-ss-EE (GSH-triggered gel).
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Liu et al.
Photo-Controllable Molecular Hydrogels for Drug Delivery
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Received: 26 February 2013. Accepted: 26 April 2013.
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