Precursor-involved and conversion rate-controlled self-assembly of a 'super gelator' in thixotropic hydrogels for drug delivery

Article abstract of DOI:10.1002/cjoc.201200237

Enzymatic hydrogelation is a totally different process to the heating-cooling gelation process, in which the precursors of the gelators can be involved during the formation of self-assembled structures. Using thixotropic hydrogels formed by a super gelator as our studied system, we demonstrated that the enzyme concentration/conversion rate of enzymatic reaction had a strong influence on the morphology of resulting self-assembled nanostructures and the property of resulting hydrogels. The principle demonstrated in this study not only helps to understand and elucidate the phenomenon of self-assembly triggered by enzymes in biological systems, but also offers a unique methodology to control the morphology of self-assembled structures for specific applications such as controlled drug release.

Full text of DOI:10.1002/cjoc.201200237

FULL PAPER
DOI: 10.1002/cjoc.201200237
Precursor-involved and Conversion Rate-controlled
Self-assembly of a ‘Super Gelator’ in Thixotropic Hydrogels for
Drug Delivery
Ou, Caiwena(区彩文)
Wang, Huaiminb(王怀民)
Chen, Minsheng*, a(陈敏生)
Yang, Zhimou*,b(杨志谋)
a Guangzhou Medical University, Guangzhou, Guangdong 510182, China
b State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin
300071, China
Enzymatic hydrogelation is a totally different process to the heating-cooling gelation process, in which the pre-
cursors of the gelators can be involved during the formation of self-assembled structures. Using thixotropic hy-
drogels formed by a super gelator as our studied system, we demonstrated that the enzyme concentration/conversion
rate of enzymatic reaction had a strong influence on the morphology of resulting self-assembled nanostructures and
the property of resulting hydrogels. The principle demonstrated in this study not only helps to understand and elu-
cidate the phenomenon of self-assembly triggered by enzymes in biological systems, but also offers a unique meth-
odology to control the morphology of self-assembled structures for specific applications such as controlled drug re-
lease.
Keywords self-assembly, hydrogel, enzymatic reaction
Introduction
of precursor and the concentration of enzyme should
play important roles in the morphology of resulting
nanostructures, thus leading to different mechanical and
optical property of the SM hydrogels.
Small molecular hydrogels (SM hydrogels)[1-8] at-
tract extensive research interests recently because they
mimic the extra-cellular matrix (ECM) and can provide
biocompatible environments for the cells, proteins, and
other bioactive molecules.[9-12] They have been widely
used in the fields of cell culture,[13-16] detection of bio-
active molecules,[17,18] drug release,[19,20] etc. The for-
mation of a three dimensional (3D) matrix that can hold
water molecules within them is crucial for the produc-
tion of an SM hydrogel. To generate such kind of 3D
matrix, external stimuli are needed to trigger the
self-assembly of small molecules, including temperature
change,[21,22] pH adjustment,[23,24] charge screening,[15]
sonication,[25,26] and chemical reactions.[27] Recently, an
enzymatic reaction was found to be a unique method to
produce SM hydrogels since the enzymes worked effi-
ciently in mild conditions.[28-31] Comparing with other
methodologies used for the formation of SM hydrogels,
enzymatic hydrogelation is more complicate due to the
presence of the precursors of SM hydrogelators, diffu-
sion of the enzyme substrates and products, and the
conversion rate of enzymatic reactions, which is similar
to the cases in biological systems such as the formation
of β-amyloid fiber. We believed that both the existence
Experimental
Chemicals
Fmoc-OSu, L-Tyr-OBu-t and other Fmoc-amino
acid were obtained from GL Biochem (Shanghai).
Chemical reagents and solvents were used as received
from commercial sources. Alkali phosphatase was pur-
chased from Takara (Dalian, P. R. China) (D2250) Bio.
Inc. Commercially available reagents were used without
further purification, unless noted otherwise. All the re-
agents such as DMF and DCM were used as received
unless noted.
General methods
1H NMR and 31P NMR (Bruker ARX 400) were
used to characterize the synthesized compounds.
ESI-MS spectrometric analyses were performed at the
Thermo Finnigan LCQ AD System. Conversion of
compound 1 was carried out by LCMS-20AD (Shima-
dzu). AFM was done on a Veeco multimode V system
with the tip of Veeco RTESP. Emission spectra were
*
E-mail: yangzm@nankai.edu.cn, gzminsheng@vip.163.com; Tel.: 0086-20-61648001
Received March 14, 2012; accepted April 22, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200237 or from the author.
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detected on a Perkin-Elmer LS-55 luminance spec-
trometer at excitation wavelength of 272 nm. Rheology
test was done on an AR 2000ex (TA instrument)
system, 40 mm parallel plates were used during
the experiment at the gap of 500 μm.
general moiety for the construction of molecular gela-
tors with excellent gelation ability.[33]
Scheme 1 Chemical structure of the precursor of an SM hy-
drogelator and schematic hydrogelation catalyzed by phosphatase
OR
Hydrogel formation
2.0 mg compound 1 and 1 equiv. of Na2CO3 (to neu-
tralize the phosphoric acid on 1) were dissolved in 1.0
mL PBS buffer (pH＝7.4), and then 1.0, 3.0, 5.0, and
7.0 μL of alkaline phosphatase (30 U/μL) was added
(final enzyme concentration＝30, 90, 150, 210 U/mL)
to form gel I, gel II, gel III and gel IV, respectively. The
gel with 0.192 wt% of 2, 0.008 wt% of 1, and 1 equiv.
of Na2CO3 was formed by a heating-cooling cycle as gel
V.
O
O
H
H
N
N
OH
N
N
H
H
O
O
O
O
P
OH
OH
Nap-GFFYp (1)
Phosphatase
Nap-GFFY (2)
R =
Releasing of ciprofloxacin from gel I and gel III
R = H
After 1.0 mL of gel I and gel III were formed by the
enzyme (1 h after the addition of the phosphatase), 0.1
mL of PBS buffer solution of ciprofloxacin at different
concentration of 3, 5, 8, and 15 mg/mL was added to
each gel, respectively. 60 seconds’ vortexes were ap-
plied to the resulting mixtures, and then the solutions
were kept at room temperature overnight (gelation was
observed less than 1 h for both gels after the vortex (de-
termined by invert-tube method), which meant that the
addition of ciprofloxacin helped the recovery of the
gels). 2.0 mL of PBS buffer was added to the top of
both gels. 10 μL of upper PBS solutions at different
time points were taken out for UV absorbance meas-
urement at 277 nm (the PBS solutions on gels without
ciprofloxacin were used as controls. And actually the
UV absorbance intensity of the control samples is near
zero). And then the releasing profiles were calculated.
The experiments were repeated for three times.
We also studied the relationship between the con-
version ratio and the gel/sol phase of our system with
different concentrations of 1 and the enzyme. As shown
in Figure 1, samples with lower initiate concentrations
of 1 needed higher conversion percentages of 1 to 2 for
the formation of the hydrogels. For examples, the con-
version percentage of 1 to 2 was 75%, 58%, 46%, 42%,
and 39% for gel I with 0.10, 0.15, 0.25, 0.30, and 0.50
wt% of 1, respectively. Comparing the results from the
samples with the same initiate concentrations of 1 but
treated with different amounts of the enzyme, samples
treated with higher concentrations of the enzyme obvi-
ously needed higher conversion percentages of 1 to 2
for the formation of the hydrogels. Though the reasons
remained unclear for why samples treated with higher
concentrations of the enzyme needed higher conversion
ratios for gelation, this result implied that higher con-
centrations of the enzyme (higher conversion rates)
would lead to weaker hydrogels with smaller G' values.
Results and Discussion
Gelation properties
100
To investigate the influence of enzyme concentration
on the property of the resulting hydrogels, the gels
formed by treating PBS (pH ＝ 7.4) solutions of
Nap-GFFYp (1 in Scheme 1) with different amounts of
phosphatase were studied. Four kinds of enzyme con-
centrations (30, 90, 150, 210 U/mL) were used to trigger
the formation of SM hydrogels (gel I, gel II, gel III and
gel IV, respectively, initiate concentration of 1＝0.2
wt% in all gels).[32] It was found that the conversion
percentages of 1 in all hydrogels after being incubated for
1 h were similar—about 96% of 1 being converted to 2
(Nap-GFFY in Scheme 1). And a gel with 96 wt% of 2
and 4 wt% of 1 was prepared by a heating-cooling cycle
(gel V) as a control. The minimum gelation concentra-
tion of 1 was about 0.08 wt% by the enzyme, which
meant that one molecule of 1 could gel more than 54000
H2O molecules after the enzymatic conversion. This
result also indicated that Nap-GFFY could be used as a
30 U/mL
150 U/mL
90 U/mL
210 U/mL
80
60
40
20
0
gel phase
solution phase
0.1
0.2
0.3
0.4
0.5
Initial concentration of 1/wt%
Figure 1 A diagram to illustrate the relationship between the
gel/sol phase and the percentage of conversion of 1 to 2 for sam-
ples with different initiate concentrations of 1 and treated with
different concentrations of the enzyme.
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Self-assembly of a ‘Super Gelator’ in Thixotropic Hydrogels for Drug Delivery
Rheology
The dynamic time sweep was used to investigate the
force than that of gel III. The critical strain value of gel
I was about 12.2%. However, this value for gel III was
larger than ca. 30%. These results indicated that gels
formed by higher amounts of the enzyme could show
better resistant properties to external stress than those
formed by lower amounts of the enzyme.
conversion rate of enzymatic gelations by different
amounts of enzyme. As shown in Figure 2, less time
was needed for the gelation of PBS solutions containing
0.2 wt% of 1 treated with higher amounts of phos-
phatase—the gelation time was about 3 min, within 1.5
min, and within 1 min for gel I, gel II/gel III, and gel IV,
respectively.[32] The gelations were nearly complete af-
ter being incubated for 1 h, indicated by both the values
of G' and G" reaching plateaus. However, as shown in
the supporting information, the final values of G' (elas-
ticity) of the gels were different—about 360, 250, 130,
and 100 Pa for gel I, gel II, gel III, and gel IV, respec-
tively.[32] These results indicated that less amount of
enzyme (lower conversion rate) led to gels with higher
elasticity and vice versa.
The dynamic strain sweep at the value of frequency
near zero (0.1 Hz in our experiments) provided useful
information on the yielding property of the hydrogels.
As shown in Figure 3A and 3C, though gel I formed by
a less amount of the enzyme (lower conversion rate)
possessed a bigger value of the elasticity than that of gel
III, gel I exhibited a weaker tolerance to the external
To our surprise, the incorporation of the ciproflox-
acin into the gels could enhance the elasticity of the gels.
As shown in Figure 3, gel I containing 1.5 wt% of the
ciprofloxacin exhibited a bigger value of G' (about 1060
Pa in Figure 3B) than that of gel I without the cipro-
floxacin (about 360 Pa in Figure 3A). However, gel I
with ciprofloxacin showed a smaller critical strain value
(11.3%) than the one without ciprofloxacin (12.2%). For
gel III, we also observed a slightly enhancement of elas-
ticity for the gel with the ciprofloxacin—about 190 Pa
and about130 Pa for gel III with and without 1.5 wt% of
the ciprofloxacin, respectively. However, gel III with
the drug showed a weaker resistance to the external
stress than gel III itself—the critical strain value for gel
III with the drug was about 12%, while this value for gel
III itself was about 30%. These results implied that the
incorporation of the ciprofloxacin would make the
nanostructures in the gels more rigid and brittle.
Figure 2 Dynamic time sweep of PBS buffer solutions containing 0.2 wt% of 1 with different concentrations of the phosphatase. (A) 30,
(B) 90, (C) 150, and (D) 210 U/mL, strain＝2% and frequency＝2 rad/s.
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Figure 3 Dynamic strain sweep of (A) gel I formed by treating a solution containing 0.2 wt% of 1 with 30 U/mL of the phosphatase, (B)
gel I with 1.5 wt% of the ciprofloxacin, (C) gel III formed by treating a solution containing 0.2 wt% of 1 with 150 U/mL of the phos-
phatase, and (D) gel III with 1.5 wt% of the ciprofloxacin, frequency＝0.1 Hz (the arrows indicate critical strain values).
Morphology
Atomic force microscopy (AFM) was used to char-
dicated that enzymatic reaction led to more ordered
structures in this system. It also suggested that the re-
sulting nanostructures might be controlled by the con-
version rate of the enzymatic reaction.
acterize the nanostructures within the gels (Figure 4).
Nanospheres with diameter of about 25—45 nm and
nanofibers with width of 25—60 nm and length of ＞1
μm were observed in gels I—III. However, the ratio
between the nanosphere and the nanofiber was obvi-
ously different—there was higher percentage of nano-
spheres in gel I and higher percentage of nanofibers in
gel III, suggesting that a less amount of the enzyme (a
lower conversion rate) led to the smaller aggregate of
nanosphere and a high concentration of the enzyme (a
higher conversion rate) led to the bigger aggregate of
nanofibers. This result correlated well with the results
obtained by the rheological measurement in Figure 3A
and 3C that gel III possessed a better resistance to ex-
ternal stress than gel I. This phenomenon was also par-
tially proved by the AFM image of gel IV, in which
nanofibers (18—50 nm) were dominated. Interestingly,
helical nanofibers and no nanospheres could be seen in
gel V formed by the heating-cooling cycle. Comparing
with the nanofibers in gels formed by the enzymatic
reaction (gel I—IV) and the heating-cooling cycle (gel
V), their size was more uniform in gel I—IV (18—60
nm) than that in gel V (15—100 nm). These results in-
Emission
Fluorescence microscopy was also used to charac-
terize the process of the enzymatic hydrogelation and
the interaction between naphthalene groups on 1 and 2
in solution and in gel phase. As shown in Figure 5A, 1
in solution exhibited distinct peaks at 327 and 336 nm,
which correspond to the 1Lb transition of naphthalene.[34]
The shoulder peak at 350—400 nm suggested that 1
formed small aggregates in solution phase.[34] The emis-
1
sion peak from Lb transition of naphthalene kept a
red-shift by time after the addition of the enzyme. And
this red shift was nearly finished at 60 min post incuba-
tion, which was consistent with the rheological meas-
urements in Figure 2. The more pronounced peaks at
350—400 nm from the gels suggested that naphthalene
groups were restricted in gel phase. Comparing the
emission pattern of gels formed by different amounts of
enzyme at 60 min, they showed slight differences—their
emission peaks were centered at 347.9, 346.1, 345.7,
and 345.3 nm for gel I, gel II, gel III, and gel IV, re-
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Self-assembly of a ‘Super Gelator’ in Thixotropic Hydrogels for Drug Delivery
Figure 4 AFM images of different hydrogels (AFM was done on a Veeco multimode V system with the tip of Veeco RTESP).
Figure 5 Emission spectra (λexcitation＝272 nm) of (A) sol. of 1 and gel I at different time points and (B) sol. of 1 and gel I—V at 60 min.
spectively, which also suggested that lower conversion
rate would lead to more efficient packing of naphthalene
groups in the gel phase. The emission pattern of gel V at
60 min was similar to gels formed by enzyme at short
time such as gel I at 1 min, which implied that the heat-
ing-cooling process led to the most irregular molecular
arrangements in the gel phase. And this result was con-
sistent with the fact that gel V had the lowest elasticity
within all the gels.[32]
also meant that gel I possessed a slow recovery property.
However, its recovery property could be improved by
the incorporation of the ciprofloxacin. As shown in the
supporting information, about 82% of the initial elastic-
ity of the gel I with the drug was achieved after 45 min
and this value was higher than 90% at the time point of
60 min. Since thixotropic hydrogels had been success-
fully applied for the delivery of cell-gel constructs and
therapeutic agents,[35,36] the possibility of the gels in this
study for drug delivery was studied. The drug molecule
of ciprofloxacin was homogeneously incorporated into
gel I and gel III (1 h post hydrogenation) by the vortex
for 1 min and being kept at room temperature overnight.
And then the releasing profile of the drug was measured.
Since the loading amount of the drug was very impor-
tant to the resulting releasing profile, we encapsulated
the ciprofloxacin in both gel I and gel III at four kinds
of concentrations (0.3, 0.5, 0.8, and 1.5 mg/mL). As
shown in Figure 6C and 6D, both gels exhibited higher
released percentages of the ciprofloxacin when the
loading amounts of the drug were lower. For example,
the releasing percentage of ciprofloxacin from gel I was
Drug release from thixotropic hydrogels
We also found that gels I—IV were thixotropic,
which meant that they could change to liquid-like fluids
upon shaking probably due to the weak matrixes formed
by nanospheres and nanofibers. As shown in Figure 6A,
gel I could change to a slightly opaque solution by a
gently hand-shaking for seconds. And it took long time
for the resulting solution to recover to its original gel
stage (about 6 h at room temperature). The dynamic
time sweep was used to study the recovery of partially
breakdown gel I (Figure 6B)—only about 40% of the
mechanical strength was achieved after 45 min, which
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Figure 6 (A) from left to right: Optical images of gel I, the solution from gel I obtained by hand-shaking for 10 s, and the recovered gel
I 6 h post shaking, (B) the recovery of gel I from partially breakdown by external shear force (the gel was first applied with the large
strain of 50% for 10 min and then the recovery was probed at the strain of 2% and frequency of 2 rad/s), and releasing profile of cipro-
floxacin from (C) gel I and (D) gel III with different concentration of Ciprofloxacin.
volved during the self-assembly of 2 due to their similar
chemical structures;[37] upon low enzyme concentration/
slow conversion rate, the local concentration of 2 gen-
erated by the enzyme was low and it had a big chance to
be surrounded by surfactant-like 1 to form nanospheres;
while a high concentration of the enzyme/ high conver-
sion rate would lead to a high local concentration of 2
that tended to form aggregates by themselves. It meant
that both the existence of precursors and the conversion
rate of enzymatic reactions had big influences on the
resulting self-assembled nanostructures in enzyme-trig-
gerd self-assembled systems. The result of drug releas-
ing profile suggested that the morphology of nanostruc-
tures on hydrogels also had influences in the affinity of
the hydrogels to drug molecules. The study in this paper
might offer a simple method of using different amounts
of enzyme to control the morphology of self-assembled
nanostructures. And our system might provide a simple
platform to control the activity of encapsulated cells,[37]
drug molecules, etc.
about 56%, 42%, 36%, and 31% when the concentration
of ciprofloxacin in it was 0.3, 0.5, 0.8, and 1.5 mg/mL,
respectively. Comparing the releasing profiles of both
gels in Figure 6C and 6D, gel III possessed a slightly
faster releasing rate than gel I when the concentration of
the ciprofloxacin within them was the same—the re-
leasing percentage of ciprofloxacin from gel III was
about 58%, 46%, 37%, and 33% when the concentration
of ciprofloxacin in it was 0.3, 0.5, 0.8, and 1.5 mg/mL,
respectively probably due to the larger total surface area
of the nanospheres in gel I than that of the nanofibers in
gel III (gels with larger total surface areas could have
higher affinities to the component within them). Though
there was only a small difference between the releasing
profiles from both gels, this result suggested that using
different concentrations of enzyme to control the mor-
phology of resulting nanostructures in hydrogels might
provide a novel strategy for controlled drug release.
Conclusions
Acknowledgement
Based on above information, we proposed a possible
mechanism of the precursor-involved and conversion
rate-controlled self-assembly—the precursor was in-
This project was partially supported by National
Natural Science Foundation of China (No. 31070856).
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Self-assembly of a ‘Super Gelator’ in Thixotropic Hydrogels for Drug Delivery
2009, 131, 5321.
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