Hydrogels generated by low-molecular-weight PEGylated luteolin and α-cyclodextrin through self-assembly for 5-fluorouracil delivery

Article abstract of DOI:10.1039/c6ra20851g

Hydrophobic luteolin (LUT) was conjugated to the oligomeric chain of methoxypoly(ethylene glycol) (mPEG) to form novel amphiphilic mPEG₁₉₀₀-LUT conjugates. Then mPEG₁₉₀₀-LUT, by using its adjacent 3′ and 4′ hydroxyl groups, were asse

Full text of DOI:10.1039/c6ra20851g

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Hydrogels generated by low-molecular-weight
PEGylated luteolin and a-cyclodextrin through
self-assembly for 5-fluorouracil delivery†
Cite this: RSC Adv., 2016, 6, 95812
a
a
a
ac
Weixia Qing,ab Yong Wang, Huan Li, Jinhua Zhu and Xiuhua Liu
*
Hydrophobic luteolin (LUT) was conjugated to the oligomeric chain of methoxypoly(ethylene glycol)
(mPEG) to form novel amphiphilic mPEG1900–LUT conjugates. Then mPEG1900–LUT, by using its
adjacent 30 and 40 hydroxyl groups, were assembled with magnetic Fe3O4 particles in an aqueous
solution to form mPEG1900–LUT–Fe3O4 conjugates, which formed hybrid Fe3O4 particles. The spectral
properties and micellization of the conjugates were studied. Both mPEG1900–LUT and mPEG1900–LUT–
Fe3O4 conjugates were able to self-assemble into stable supramolecular hydrogels through a-
cyclodextrin (a-CD) in water, and their gelation times and temperatures were determined. The hydrogels
displayed typical porous structures, which are suitable for drug delivery. Therefore, 5-fluorouracil (5-FU)
was loaded into the formed hydrogels to control its release in vitro. The drug release observations
showed that introducing Fe3O4 particles into the hydrogel improved the sustained release effect.
Received 19th August 2016
Accepted 23rd September 2016
DOI: 10.1039/c6ra20851g
www.rsc.org/advances
are desirable for use as drug delivery and controlled release
systems.
1. Introduction
Luteolin (LUT, 30,40,5,7-tetrahydroxyavone) is well known as
Hydrogels have been recently utilized for controlled drug
release, because of their excellent hydrophilicity, biocompati-
bility and low inammatory response.1–3 Hydrogels composed
of polyrotaxane constitute an important class of remarkable
materials that are formed by a linear polymer chain threading
through a series of cyclodextrin (CD) cavities.4–6 Polyrotaxane
hydrogels have been reported to be endowed with tunable
temperature-responsive potentials. So it is very benecial to
develop effective polyrotaxane hydrogels as delivery systems.7,8
Poly(ethylene glycol) (PEG) has also been found to be able to
thread through a-CD molecules of polyrotaxane.9–12 It has been
quite generally stated in the literature that, a high molecular
weight (MW > 10k) PEG is necessary for chemical and physical
hydrogels. However, water-soluble polymer chains with high
molecular weights (normally MW > 10k) are known to be
unsuitable for ltration through the human kidney membrane
because of their large hydrodynamic radii.13 Therefore, suitable
procedures for preparing hydrogels based on low-MW PEGs and
that can be used in pharmaceutical or medicinal applications
a avonoid, which mostly exists in various vegetables, fruits and
medicinally important plants. LUT has been shown to display
anticancer,14–17 anti-inammatory,18 anti-allergic19 and anti-
amnesic20 activities. Nevertheless, the application of LUT is
hampered, due to its poor solubility.21
For the current work, we took into consideration the strong
hydrophobicity of LUT to pursue the formation of novel
amphiphilic conjugates using LUT as the hydrophobic part of
the conjugate. LUT was linked to the terminal group of low-MW
(1.9k) methoxy PEG (mPEG) to synthesize novel amphiphilic
mPEG–LUT conjugates, which can self-assemble into nano-
particles with a core–shell structure in aqueous solutions. The
mPEG–LUT conjugates, due to their having adjacent hydroxyl
groups at the 30 and 40 positions, reacted with Fe3O4 particles to
form hybrid nanoparticles. It is noteworthy that we succeeded
in constructing hydrogels based on the complexes of a-CD and
low-MW mPEG–LUT. At the same time, 5-FU was used as
a model drug for investigating the performance of the hydrogels
in drug loading and release.
aInstitute of Environmental and Analytical Sciences, College of Chemistry and
Chemical Engineering, Henan University, Kaifeng, 475004, P. R. China. E-mail:
ll514527@163.com
bMedical College, Henan University, Kaifeng, 475004, P. R. China
cKey Lab. of Natural Medicine and Immune-engineering of Henan Province, Henan
University, Kaifeng, 475004, P. R. China
2. Materials and methods
2.1. Chemicals and materials
LUT and mPEG (MW ¼ 1.9k) were purchased from Sigma-
Aldrich. Cesium carbonate, benzyl bromide, 4-toluene sulfonyl
chloride and anhydrous dimethyl formamide were purchased
from J&K Chemical Technology (Beijing China). All other
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra20851g
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chemicals were of analytical grade and supplied by Sinopharm and precipitated in ethyl ether three times at 0 ꢀC. Compound 4
Chemical Reagent Co., Ltd (Shanghai, China).
was recovered as a pale yellow powder (0.58 g, 90%). The
chemical structure of this product was characterized by
1
1
analyzing its H-NMR spectrum (Fig. S4†). H NMR (400 MHz,
DMSO-d6): d 7.690 (s, 1H), 7.628 (d, 1H, J ¼ 8.8 Hz), 7.520–7.317
(m, 15H), 7.225 (d, 1H, J ¼ 8.8 Hz), 6.971 (s, 1H), 6.733 (s, 1H),
6.619 (s, 1H), 5.275 (s, 2H), 5.253 (s, 2H), 5.247 (s, 2H), 4.168 (t,
2H, J ¼ 4.4 Hz), 3.815–3.242 (mPEG chain).
2.2. Preparation of Fe3O4 particles
FeCl3$6H2O, then sodium carboxymethylcellulose (CMC-Na)
and nally sodium acetate anhydrous (NaAc) were dissolved
in ethylene glycol. The mixture was transferred into a Teon™-
lined autoclave, kept at 200 ꢀC for 10 h and then cooled to room
temperature. The solid black products were collected and kept
for later use on the basis of ref. 22.
Synthesis of 5. A solution of compound 4 (0.57 g, 0.23 mmol)
in 50 mL of dry methanol was cooled to 0 ꢀC, and to this mixture
we slowly added 5% Pd (0) on activated carbon (0.19 g, 0.03
mmol) under a hydrogen atmosphere. The mixture was stirred
overnight, aer which it was ltered. The methanol was then
2.3. Synthesis of mPEG–LUT conjugates
Synthesis of 2. LUT (1) (0.10 g, 0.35 mmol), anhydrous K2CO3 evaporated, and the resulting light yellow residue was dissolved
(0.20 g, 1.41 mmol) and KI (0.01 g, 0.07 mmol) were dried under in a minimal amount of water and extracted three times with
ꢀ
vacuum at 60 C and then dissolved in dry DMF (5 mL) under CH2Cl2. The organic phase was washed with deionized water.
a nitrogen atmosphere. Aer 1 h at room temperature, the The solution was dried with anhydrous MgSO4. The ltrate was
reaction mixture was treated with benzyl bromide (0.30 mL, 2.52 concentrated and precipitated in ethyl ether three times.
mmol) and then heated to 80 ꢀC for 10 h. Deionized water was Compound 5 was recovered as a pale yellow powder (0.36 g,
added into the mixture, and then the mixture was extracted with 72%). The chemical structure of this product was characterized
CH2Cl2 three times. The organic phase was washed with 0.5 mol by analyzing its 1H-NMR spectrum (Fig. S5†). 1H NMR (400
HCl and saturated brine. The solution was dried with anhy- MHz, DMSO-d6): d 10.677 (broad, 1H), 9.683 (broad, 1H), 9.474
drous MgSO4. Aer the solvent was removed in vacuo, the (s, 1H), 7.312–7.300 (m, 2H), 6.858 (d, 1H, J ¼ 8.8 Hz), 6.489 (d,
resulting residue was puried by using column chromatography 1H, J ¼ 1.6 Hz), 6.374–6.359 (m, 2H), 4.089 (t, 2H, J ¼ 4.4 Hz),
with a silica gel and with CH2Cl2 as the eluent to give the stra- 3.803–3.233 (mPEG chain).
mineous solid product 2 (0.14 g, 71%). The chemical structure
of this product was characterized by analyzing its 1H-NMR 2.4. Synthesis of mPEG–LUT–Fe3O4 conjugates
1
spectrum (Fig. S2†). H NMR (400 MHz, DMSO-d6): d 7.734 (d,
A mass of 15 mg of Fe3O4 particles was dispersed completely in
1H, J ¼ 2 Hz), 7.668 (dd, 1H, J ¼ 8.4 Hz, J ¼ 2 Hz), 7.309–7.509
5 mL double-distilled water, to which a volume of 5 mL of the
(m, 15H), 7.215 (d, 1H, J ¼ 8.4 Hz), 7.005 (s, 1H), 6.865 (d, 1H, J
¼ 2 Hz), 6.452 (d, 1H, J ¼ 2 Hz), 5.260 (s, 2H), 5.236 (s, 2H), 5.220
(s, 2H); MS (ESI, m/z): 579.20 [M + Na+].
mPEG–LUT solution (4 mg mLꢁ1) was then added under soni-
cation for 40 minutes. Then the aqueous phase was separated,
freeze-dried, and mPEG–LUT–Fe3O4 was obtained.
Synthesis of 3. A solution of 30% NaOH in water (5 mL) and
15 mL of CH2Cl2 was added to mPEG1900 (1.00 g, 0.53 mmol).
The vigorously stirred mixture was dropwise added to a solution
of 1.50 g (7.87 mmol) of tosyl chloride in CH2Cl2 (15 mL) over 1
h. The organic layer was then separated and washed with water
three times. The volume of CH2Cl2 was reduced by 95% under
reduced pressure. The remaining CH2Cl2 was cooled to 0 ꢀC,
and 50 mL of anhydrous ether was slowly added to this CH2Cl2
with stirring. Aer 4 h, compound 3 (0.88 g, 81%) as a white
powder was recovered by ltration and washed four times with
100 mL of diethyl ether. The chemical structure of this product
was characterized by analyzing its 1H-NMR spectrum (Fig. S3†).
2.5. Characterizations of the conjugates
The FTIR spectra were recorded on a Thermo Nicolet Avatar 360
spectrometer in transmittance mode using KBr pellets. UV-Vis
spectroscopic studies were carried out using a TU-1900 spec-
trophotometer (Beijing Purkinje General Instrument Co. Ltd.).
The saturation magnetization was obtained using an MPMS3
(Quantum Design, US). The zeta potential was recorded using
ꢀ
a Malvern Nano-ZS90 instrument at 25 C.
2.6. Preparation of blank and 5-FU loaded hydrogels
1H NMR (400 MHz, CDCl3): d 7.744 (d, 2H, J ¼ 8 Hz), 7.296 (d, One aqueous solution sample of a-CD (80.0 mg mLꢁ1) was
2H, J ¼ 8 Hz), 4.103 (t, 2H, J ¼ 4.8 Hz), 3.765–3.326 (mPEG added to an aqueous solution of mPEG–LUT, and another to
chain), 2.723 (s, 3H), 2.399 (s, 3H).
mPEG–LUT–Fe3O4, and for both resulting samples, the
Synthesis of 4. Compound 2 (0.15 g, 0.26 mmol) and Cs2CO3 concentration was 10 mg mLꢁ1. Each composition was mixed
(0.34 g, 1.05 mmol) were dissolved in 5 mL of DMF under thoroughly by sonication for about 2 min followed by incuba-
a nitrogen atmosphere. Aer 0.5 h at room temperature, tion at room temperature for 72 h before taking measurements.
compound 3 (0.53 g, 0.26 mmol) dissolved in 5 mL of DMF was The gelation times of the supramolecular hydrogels were esti-
added into the compound 2/Cs2CO3/DMF solution. The result- mated using a vial-tilting method. The timer was started
ing mixture was stirred for 20 h at room temperature and then immediately aer mixing the two components and the gelation
heated to 70 ꢀC for 5 h. Deionized water was added into this time recorded was when no ow was observed for at least 1 min.
mixture, which was then extracted three times with CH2Cl2. The Meanwhile, an a-CD (80.0 mg mLꢁ1) solution and 5.0 mg of 5-
organic phase was washed with deionized water. The solution FU were added to 1.0 mL of an aqueous solution of mPEG–LUT
was dried with anhydrous MgSO4. The ltrate was concentrated and mPEG–LUT–Fe3O4 (10 mg mLꢁ1), respectively. Each
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resulting composition was mixed thoroughly by sonication for
about 2 min followed by incubation at room temperature for 72
h before measurements were taken.
2.7. In vitro drug release study
The 5-FU-loaded mPEG–LUT and mPEG–LUT–Fe3O4 supramo-
lecular hydrogels were prepared in respective 1.5 mL reagent
bottles. Each reagent bottle was placed upside-down in a dial-
ysis bag with 15 mL of pH 7.4 phosphate-buffered (PBS) solu-
tion, which was incubated in 100 mL of PBS at 37 ꢀC with gentle
shaking. At predetermined time points, 3 mL of release medium
was withdrawn and the same volume of fresh PBS solution was
added to maintain
a constant volume. The cumulative
percentage release (Q%) was calculated using the equation
nꢁ1
X
Cn ꢂ V0 þ Vi
Ci
i¼1
Q% ¼
ꢂ 100
m
where Cn (mg mLꢁ1) is the concentration of drug in the sample,
V0 (mL) is the volume of the release medium, Vi (mL) is the
volume of the replaced medium, and m (mg) is the mass of the
drug in the sample.
Fig. 1 1H NMR spectra of mPEG–LUT in DMSO-d6 (A) and D2O (B).
3. Results and discussion
3.1. Design and synthesis of mPEG–LUT conjugates
1
out H-NMR spectroscopy in DMSO-d6 and D2O.23,24 DMSO was
used as a non-selective solvent for both mPEG and LUT moieties,
whereas water was used as a selective solvent that dissolved the
mPEG well but was a poor solvent for LUT. In DMSO, both mPEG
and LUT moieties gave rise to sharp peaks, indicative of their
rapid molecular motions (Fig. 1A). However, in D2O, mPEG
moieties gave a sharp peak, but LUT peaks were no longer sharp
and were greatly reduced in intensity, indicating the formation
of core/shell structures with relatively few LUT segments while
the hydrophilic mPEG segments still moved freely in the water
(Fig. 1B). The mPEG interacted with water molecules via
hydrogen bonds, forming an exterior hydrophilic corona
extending into the aqueous medium and stabilizing the micelle
structure. The results conrmed that mPEG–LUT can self-
assemble into a core/shell micelle structure in water.
The FT-IR and UV-Vis spectra of both mPEG–LUT and
mPEG–LUT–Fe3O4 conjugates are shown in Fig. 2. As seen
Fig. 2A, an Fe–O bending vibration peak of Fe3O4 was observed
at about 594 cmꢁ1 in the spectrum of Fe3O4, but it shied to 530
cmꢁ1 in the spectrum of mPEG–LUT–Fe3O4 because the Fe3O4
reacted with the 30 and 40 adjacent hydroxyls. The Fe–O bending
vibration peak of mPEG–LUT–Fe3O4 was very weak because of
the low amount of Fe3O4 in the mPEG–LUT–Fe3O4; only 2.15%
of the mPEG–LUT–Fe3O4 consisted of Fe3O4 according to
Inductive Coupled Plasma Emission Spectrometer (ICP).
The syntheses of mPEG–LUT conjugates are shown in Scheme 1.
LUT (1) was reacted with benzyl bromide to give 2, which is
a crucial intermediate. During this synthetic process, the
experimental results revealed the deprotonation of 1 with
K2CO3 (4 equiv.) to be highly selective. Only the proton of the
hydroxyl on the 5-position could not be removed. Coupling of 2
with 3 gave 4, which was deprotected with palladium(0) on
carbon to give 5.
3.2. Characterizations of conjugates
Both mPEG–LUT and mPEG–LUT–Fe3O4 conjugates had
amphiphilic structures, which were able to self-assemble into
stable micelles in aqueous solutions. As shown in Fig. S6,† the
average sizes of mPEG–LUT and mPEG–LUT–Fe3O4 conjugate
micelles were measured to be about 318.5 nm and 286.9 nm with
polydispersity indexes of 0.310 and 0.348, respectively. Further-
more, the micellization of mPEG–LUT was studied by carrying
As seen Fig. 2B, the ultraviolet absorption peak of mPEG–
LUT at 354 nm sharply shied to 379 nm aer Fe3O4 reacted
with the 30 and 40 adjacent hydroxyls. Meanwhile, analysis of the
magnetization curves of mPEG–LUT–Fe3O4 conjugates, shown
in Fig. 2C, indicated the saturation magnetization value to be
about 2.2 emu gꢁ1. This value is much smaller than the 80 emu
Scheme 1 Synthetic route of mPEG–LUT conjugates.
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Scheme 2 Schematic representation of the supramolecular hydrogels
made of conjugates and 5-FU with a-CD.
Fig. 3 Optical photograph of (A) mPEG–LUT/a-CD sols before being
converted to gels, (B) mPEG–LUT/a-CD supramolecular hydrogels, (C)
mPEG–LUT–Fe3O4/a-CD sols before being converted to gels, and (D)
mPEG–LUT–Fe3O4/a-CD supramolecular hydrogels.
gradually formed (Fig. 3). The hydrogels have been shown to be
comprised of mPEG/a-CD complexes.25,26 Both a-CD and mPEG–
LUT provided the supra-cross-links, which are particularly
favorable to the gelation process. Both G1 and G2 exhibited
a reversible gel–sol transition with a change in temperature.
They started out mobile above a certain temperature, while they
returned to an opaque gel phase aer cooling to below this
temperature. Meanwhile, G1 and G2 were found to be thermo-
sensitive at about 40 ꢀC, which is an acceptable temperature for
site-specic drug delivery. In addition, introduction of Fe3O4
particles showed remarkable positive effects on gelation time,
reducing it from 20 min to 5 min. Perhaps the Fe3O4 particles
promoted the gelation process by contributing to the coordi-
nation interactions between the metal and polar groups.
The hydrogels were kept for 72 h aer formation, and freeze-
ꢀ
dried under a vacuum at ꢁ54 C for 24 h. Their morphologies
Fig. 2 FT-IR spectra (A) and UV-Vis spectra (B), and magnetization
curves (C) of mPEG–LUT–Fe3O4 conjugates.
were studied using a JSM-7001F (JEOL Co., Japan), as shown in
the images of Fig. 4. G1 and G2 each clearly displayed a typical
gꢁ1 value for Fe3O4 (see Fig. S1†), and this difference mainly
derived from the different amount of Fe3O4 in the mPEG–LUT–
Fe3O4 conjugates.
3.3. Formation of blank and 5-FU loaded hydrogels
A schematic representation of the supramolecular hydrogels
made of mPEG–LUT (or mPEG–LUT–Fe3O4) conjugates and 5-
FU with a-CD is shown in Scheme 2. Solutions of a-CD were
added to mPEG–LUT and mPEG–LUT–Fe3O4 micelles, respec-
tively, and the resulting compositions were mixed thoroughly by
sonication. As expected, homogeneous hydrogels G1 and G2 Fig. 4 SEM images of G1 and G2.
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Acknowledgements
This work was supported by the Support Plan of Science and
Technology Innovation team in Universities and Colleges in
Henan Province of China (No. 14IRTSTHN030), Key Project of
Science and Technology Research in Education Department of
Henan Province in China (No. 14A150011) and Key Technology
Research Program of Henan Province in China (No.
152102210257).
Notes and references
´
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˜
´
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´
´
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