Colloids and Surfaces B: Biointerfaces 113 (2014) 223–229

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Colloids and Surfaces B: Biointerfaces

journal homepage: www.elsevier.com/locate/colsurfb

Controlled release of anticancer drug using graphene oxide as a

drug-binding effector in konjac glucomannan/sodium alginate
hydrogels
Jia Wang, Changhua Liu ∗ , Ying Shuai, Xiaoyan Cui, Ling Nie
College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China

a r t i c l e i n f o a b s t r a c t

Article history: In order to find new composite materials for the controlled release of drugs, a series of novel pH sensitive
Received 28 April 2013 konjac glucomannan/sodium alginate (KGM/SA) and KGM/SA/graphene oxide (KGM/SA/GO) hydrogels
Received in revised form 31 August 2013 were prepared, using GO as a drug-binding effector for anticancer drug loading and release. The hydro-
Accepted 3 September 2013
gels were characterized using Fourier transform infrared spectroscopy (FTIR), and scanning electron
Available online xxx
microscopy (SEM). The effects of component ratio and pH on the swelling properties of hydrogels were
studied. The release amount of 5-fluorouracil (5-FU) incorporated into KGM/SA/GO-3 hydrogels was
Keywords:
about 38.02% at pH 1.2 and 84.19% at pH 6.8 after 6 h and 12 h, respectively. Therefore, the release rate of
pH sensitive
Drug-binding effector
5-FU from the functionalized KGM/SA using GO could be effectively controlled, Go has a great potential
Graphene oxide to be a promising drug-binding effector for hydrogel functionalization in drug delivery.
Konjac glucomannan © 2013 Elsevier B.V. All rights reserved.

1. Introduction Recently, the preparation and application of novel biopoly-

Cancer remains a challenging health problem to human beings.
To overcome this problem, two major strategies have been
extensively studied. The first strategy involves synthesizing new
anticancer drugs. The second strategy involves developing novel
anticancer drug delivery systems [1–3] allowing for a more effec-
tive use of drugs to fight against tumors.
During the recent decades, natural biopolymers have frequently
been used as raw materials for the design of drug delivery formu-
lations owing to their excellent properties, such as non-toxicity,
biocompatibility, renewability, biodegradability and environmen-
tal sensitivity. Starch [4], guar gum [5], chitosan [6], konjac
glucomannan (KGM) [7], and sodium alginate (SA) [8] have been
used for controlled drug delivery. However, the disadvantages such
as weak mechanical properties and burst release of drugs are hard
to avoid when pristine biopolymers are used as drug carriers.
The aforementioned disadvantages are mainly due to the weak
interaction between the biopolymers and the drugs and the quick
disintegration of the biopolymer carries during the release process.
Therefore, many methods such as blending with other polymers
and grafting with monomers have been used to improve the prop-
erties of the biopolymer vehicles [9,10].
∗ Corresponding author. Tel.: +86 2368252360; fax: +86 2368254000.
E-mail address: chliu@swu.edu.cn (C. Liu).
mer/nanomaterial composites [11–13] as controlled drug delivery
vehicles have attracted much attention owing to their unique struc-
ture and properties. Graphene oxide (GO) is an ideal material for
the preparation of drug scaffolds because of its one-atom thick-
ness and oxygenated defects, which are rather suitable for covalent
and non-covalent functionalization owing to its excellent surface
activity and solution processability [14,15]. GO sheets are enriched
with oxygen-containing functional groups such as hydroxyl and
epoxide on the basal planes and carbonyl and carboxylic groups
at the sheet edges. Further, the large two-dimensional plane of GO
sheets provides large specific surface area to carry drugs via surface
adsorption, hydrogen bonding, and other types of interactions [16].
Thus, the excellent biocompatibility and nontoxicity of GO makes it
a promising material for drug carrier substances [17]. Moreover, GO
could be crosslinked by divalent and multivalent cations in aqueous
solution [18], similar to SA. However, the use of GO in drug delivery
formulations has rarely been studied.
5-Fluorouracil (5-FU), one of the major antimetabolites, has
been the most widely used chemotherapeutic agent [19] against
colorectal cancer for many decades. However, intravenous admin-
istration of 5-FU produces severe systemic toxic effects due to its
cytotoxic nature toward rapidly dividing normal cells, thus limiting
its clinical application. Therefore, the rate controlled target delivery
of 5-FU is expected to reduce systemic side effects and provide an
effective therapy involving reduced dose and treatment period for
colorectal cancer. Attempts are being made to develop methods for
the controlled release of 5-FU using different drug delivery systems.

0927-7765/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.colsurfb.2013.09.009
224 J. Wang et al. / Colloids and Surfaces B: Biointerfaces 113 (2014) 223–229
Table 1
Feed composition for the preparation of KGM, KGM/SA, and KGM/SA/GO hydrogels and drug loading (EEs).
Sample KGM (g) SA (g)
KGM 1.5 0 0
KGM/SA-1 1.125 0.375
KGM/SA-2 1 0.5
KGM/SA-3 0.75 0.75
KGM/SA/GO-1 0.75 0.75
KGM/SA/GO-2 0.75 0.75
KGM/SA/GO-3 0.75 0.75
Jin et al. reported the pH-controlled release of 5-FU from 5-FU/␤-
cyclodextrin complex intercalated in double layered hydroxide
[20]. Jin demonstrated a proof-of-concept approach for construc-
ting a novel micelle-drug conjugate system for the photo-triggered
release of 5-FU under physiological conditions [21]. However, the
degradation of carriers produced unwanted toxic effects [22].
In this study, KGM was used as the matrix to prepare more stable
intelligent hydrogels, using SA as the pH sensitive agent and GO as
drug binding effector. Furthermore, the release profiles of a model
drug, 5-FU, from the test hydrogels were studied in simulated gas-
tric and intestinal pH media. Moreover, the interaction between
5-FU and GO has been investigated by UV–vis spectroscopy.
2. Materials and methods
2.1. Materials
KGM (99%, viscosity: 1% solution, 25 ◦ C, ≥24,000 MPa s) was
obtained from Engineering Center of Southwest University of Kon-
jac Resources Research (Chongqing, China). SA (chemical grade,
viscosity: 1% solution, 25 ◦ C, 200 ± 20 MPa s) was purchased from
Taixing Chemical Co. Ltd. (Chongqing, China) and used without fur-
ther purification. Graphite powder was obtained from Shanghai
Huayi Huayuan Chemical Co. Ltd. (Shanghai, China). 5-FU was
provided by Hengshuo Chemical Co. Ltd. (Wuhan, China). Other
analytical grade reagents were used as received.
2.2. Preparation of GO
GO was prepared by the oxidation of natural graphite powder
according to the modified Hummers’ method [23]. Graphite pow-
der (3 g) and concentrated sulfuric acid (120 mL) were mixed in
an ice bath followed by the slow addition of KMnO4 (15 g) with
stirring. The rate of addition was carefully controlled to prevent
the temperature of the suspension from exceeding 20 ◦ C, ice-bath
was then removed and the temperature of the suspension brought
to 35 ◦ C and maintained for 2 h. Deionized water (250 mL) was
slowly added to the reaction mixture and the temperature was con-
trolled below 50 ◦ C for another 2 h. Subsequently, deionized water
(700 mL) and 30% H2 O2 (20 mL) were added separately, resulting in
a yellow brown mixture. Finally, the mixture was centrifuged and
washed with aqueous HCl solution (10:1, v/v) and then with deion-
ized water until the pH of the upper layer of suspension was near 7.
Dry Graphene oxide powder was obtained by drying at 50 ◦ C for 48 h
under vacuum. The GO so obtained was able to form stable aqueous
dispersion by ultra-sonication owing to its strong hydrophilicity.
2.3. Preparation of KGM/SA hydrogels
For the thorough intermixing of the polysaccharide systems,
KGM and SA were dissolved in an aqueous NaOH solution (pH 8) at
a total concentration of 1% (w/v) at room temperature, and then
mixed by mechanical stirring (400 rpm) for 4 h. To evaluate the
interaction between KGM and SA, several weight ratios of KGM
and SA (1:0, 3:1, 2:1 and 1:1) were prepared while keeping the
GO (g) H2 O (ml) Ca(OH)2 (ml) EEs (%)
150 10 10.29
0 150 10 13.32
0 150 10 15.50
0 150 10 17.49
0.15 150 10 22.73
0.30 150 10 27.09
0.45 150 10 32.04
total polysaccharide concentration at 1% (w/v). Then, a Ca(OH)2
suspension (10 mL) was added into the beaker and the speed of
mechanical was increased to 800 rpm. After 10 min, the beaker was
transferred to an oil bath and the mixture was heated at 90 ◦ C for
6 h for deacetylation and crosslinking. The obtained hydrogels were
washed five times with aqueous HCl solution (10:1, v/v) followed
by five washings with deionized water to remove small molecules
and residual base, and then dried to a constant weight at 40 ◦ C and
stored until further used. The codes of all hydrogels are listed in
Table 1.
2.4. Preparation of KGM/SA/GO nanocomposite hydrogels
The KGM/SA/GO nanocomposite hydrogels were prepared
according to the same procedure except that GO was first dissolved
in aqueous NaOH solution (pH 8), and the weight ratio of KGM and
SA was kept content at 1:1. For the evaluation of the interaction
between GO and polysaccharide, several weight ratios of GO and
polysaccharide (10%, 20% and 30%) were prepared while keeping
the total polysaccharide concentration at 1% (w/v).
2.5. Drug loading and drug content determination
The hydrogels dried in oven at 40 ◦ C for 12 h were equilibrated
in 100 mL of 50 mg/L 5-FU solution for 24 h at room temperature
in order to load the drug into the hydrogels. The difference in
5-FU concentrations between the original 5-FU solution and the
supernatant solution after the loading were measured at 265 nm
wavelength using an UV spectrophotometer (T6 New Century,
China). The entrapment efficiencies (EEs) of the matrices for 5-FU
was determined using Eq. (1) as follows:
w1
EEs = × 100% (1)
w2
where w1 and w2 are the actual and theoretical 5-FU contents of
the hydrogels. The EE of all the hydrogels are listed in Table 1.
2.6. Measurement of swelling ratio
Swelling kinetics is a very important property for a drug deliv-
ery vehicle because it has a significant influence on controlled drug
delivery behavior. First, dry hydrogels (50 mg) were immersed a
buffer solution (25 mL) consisting of pH 1.2 hydrochloric acid buffer
solution (HBS) and pH 6.8 phosphate buffer solution (PBS) in order
to simulate the pH of the human stomach and colon, respectively.
After a pre-determined interval, the swollen samples were sepa-
rated from the unabsorbed fluids by filtering through a 100-mesh
screen, blotted to remove excess fluid, and then weighed immedi-
ately. The swelling ratio of the samples at a given time (t), Qt , can
be calculated by using Eq. (2) as follows:
mt − m0
Qt = (2)
m0
where m0 and mt are the weights of the dry and swollen sample,
respectively. Qt is calculated as grams of water per gram of sample.
 J. Wang et al. / Colloids and Surfaces B: Biointerfaces 113 (2014) 223–229 225

2.7. In vitro cumulative release studies

The in vitro 5-FU release behaviors of the samples were stud-

ied using an intelligent shaking water bath incubator (SHZ-88,
China) at 70 rpm. The samples (0.200 g) were placed into the dialy-
sis chambers containing 10 mL of buffer solutions, which were then
dialyzed in 90 mL of corresponding pH 1.2 and 6.8 buffer solutions
at 37 ± 0.5 ◦ C, respectively. After a given time, 3.0 mL of the solu-
tion released was withdrawn and replaced with same amount of
fresh dissolution medium to maintain a fixed volume of the release
medium. The amount of 5-FU released was analyzed at 265 nm
using an UV–vis spectrophotometer. The percentage release of 5-FU
was determined by using Eq. (3) as follows:
Rt
Cumulative 5 − FU release(%) = × 100 (3)
L
where L and Rt are the initial amount of 5-FU loaded and cumulative
amount of 5-FU released at time t, respectively.
All the tests including the measurement of swelling ratio and
in vitro 5-FU cumulative release studies were carried out in tripli-
cate, and the average values are reported in this study.

2.8. Characterization

The Fourier transform infrared (FTIR) spectra of the hydrogels

were analyzed in KBr discs using a Nicolet (USA) 170SX FTIR spec-
trometer in the range of 4000–500 cm−1 . The micromorphologies of
the hydrogels were investigated by scanning electron microscopy
(SEM) using a Hitachi S-4800, Japan, after the samples had been
freeze-dried. All the samples were placed on round brass stubs
and sputter coated with gold and then scanned at an accelerating
voltage of 20 kV.

3. Results and discussion

3.1. Gelation and characterization of hydrogels

3.1.1. Gelation mechanism of hydrogels

KGM, KGM/SA and KGM/SA/GO hydrogels were prepared at
90 ◦ C using a Ca(OH)2 suspension. KGM formed strong, elastic, and
thermally stable hydrogels when heated with alkali by deacety-
lation and disruption of the hydrogen bonding of the hydration
between the macromolecular chain and water molecule [24]. Both
SA and GO were able to be ionically crosslinked to form the
pH sensitive hydrogels by the addition of divalent Ca2+ cations.
The possible mechanism for the gelation of KGM, KGM/SA and
KGM/SA/GO are shown in Scheme 1.
3.1.2. FTIR spectral analysis
Fig. 1(a) shows the FT-IR spectra of KGM, KGM/SA-3, and
KGM/SA/GO-3 hydrogels along with those of SA and GO. The FTIR
spectrum of GO shows a broad band for the hydroxyl(OH) groups at
3421 cm−1 , and the carbonyl and carboxylic groups bands appeared
at 1720, 1591 cm−1 , respectively [16]. Further, the IR peaks for other
C O functionalities such as C OH and C O C appeared at 1384
and 1123 cm−1 , respectively [25]. These main characteristic peaks
in the FT-IR spectrum indicated that the GO has been successfully
synthesized.
For the neat KGM hydrogel sample, the stretching and bend-
ing vibrations of OH groups occurred at 3422 and 1631 cm−1 ,
respectively. The absorption band at 1631 cm−1 is attributed to the
intramolecular hydrogen bonds [26]. Furthermore, in the FTIR spec-
trum of SA, the strong absorption bands at 1592 and 1414 cm−1
are attributed to asymmetric and symmetric stretching vibrations
of the carboxylate (COO) groups on the polymer backbone [27],
respectively, which correspond to the bands at 1592 and 1412 cm−1
Fig. 1. (a) FT-IR spectra of KGM, KGM/SA-3, and KGM/SA/GO-3 hydrogels along with
those of SA and GO; (b) FT-IR spectra of 5-FU, KGM/SA/GO-3, and KGM/SA/GO-3/5-
FU.
of the FTIR spectrum of KGM/SA-3 and at 1594 and 1413 cm−1
of the FTIR spectrum of KGM/SA/GO-3. After the formation of
KGM/SA/GO-3 hydrogel, the characteristic peaks at 3421, 1592,
and 1412 cm−1 of KGM/SA-3 shifted to 3424, 1594 and 1413 cm−1 ,
respectively, indicating that hydrogen bonding between GO and
polysaccharide has been formed in the composite hydrogels [28].
Fig. 1(b) shows the FT-IR spectra of KGM/SA/GO-3, and
KGM/SA/GO-3/5-FU hydrogels along with that of 5-FU. The FTIR
spectrum of 5-FU shows a broad band at 3133 cm−1 , which is
attributed to the N H stretching, and the bands at 1723, 1659, and
1401 cm−1 are characteristic absorption bands for the ketoimide
ring structure, enolic form, and C N stretching vibration, respec-
tively. The characteristic absorption bands of 5-FU can be observed
clearly in the spectrum of KGM/SA/GO-3/5-FU hydrogels by com-
paring the FT-IR spectra of KGM/SA/GO-3 and KGM/SA/GO-3/5-FU
hydrogels with that of 5-FU, indicating the successful entrapment
of 5-FU in the hydrogels. The characteristic peaks of the KGM
hydrogel at 3424 and 1631 cm−1 shifted to 3473 and 1634 cm−1
in the KGM/SA/GO-3 hydrogel, respectively, indicating that hydro-
gen bonding among 5-FU, GO, and polysaccharide has been formed
in the composite hydrogels.
226 J. Wang et al. / Colloids and Surfaces B: Biointerfaces 113 (2014) 223–229
Scheme 1. The possible mechanism of the gelation of KGM, KGM/SA, and KGM/SA/GO hydrogels.
3.1.3. SEM analysis
The SEM images of neat KGM, KGM/SA-3, and KGM/SA/GO-3
hydrogels provide insight into the structural information of the
products, as shown in Fig. 2. It is not easy to distinguish the polysac-
charide SA and GO nanosheets from the KGM matrix. However,
there are obvious differences in the morphologies among KGM
(Fig. 2a and d), KGM/SA-3 (Fig. 2b and e), and KGM/SA/GO-3 (Fig. 2c
and f) hydrogels. The surface of the neat KGM hydrogel showed
many pores, just like a net. The surface of KGM/SA-3 hydrogel
showed a multi-plated structure with larger gaps among the leaf-
like plates compared to the pores of the neat KGM hydrogel, owing
to the mutual repulsion between the dissociative COO groups of SA.
However, the surface of KGM/SA/GO-3 exhibits the most compact
structure among these hydrogels, just like a tight flower bud. This
may be attributed to the presence of GO forming physical crosslinks
with SA and KGM [29]. When GO is added, the dissociative COO
groups of SA could be crosslinked with COO groups of GO by Ca2+
cations to create calcium carboxylate ( COO. . . Ca. . . OOC ) bonds.
Further, the OH and epoxide functional groups present on the basal
planes of GO may form strong hydrogen bonds and other types of
interactions with SA and KGM. Thus, the introduction of GO not
only reduces the mutual repulsion between the dissociative COO
groups of SA, but also enhances the molecular interaction in the
hydrogels.
3.2. Swelling kinetics
To simulate the physiological condition in the stomach and
small intestine, the swelling kinetics of the hydrogels in different
buffer solutions (pH 1.2 and 6.8) were investigated at 37 ± 0.5 ◦ C
and the results are shown in Fig. 3. The swelling ratios of all the
hydrogels increased very lowly with increasing time at pH 1.2
(Fig. 3a). The swelling ratio of KGM hydrogels was found to be
the lowest compared to those of KGM/SA and KGM/SA/GO hydro-
gels because the swelling of KGM hydrogel cannot be reversed
after losing water to become a dry hydrogel. The swelling ratio of
KGM/SA hydrogels increases with increasing SA content owing to
large gaps on the surface of KGM/SA hydrogels, which can easily
absorb and store water. However, the swelling ratio of KGM/SA
hydrogels is still less than 3.5 because the carboxylic acid groups
of SA can form strong hydrogen bands at a low pH, resisting water
penetration. However, the swelling ratio of KGM/SA/GO hydrogels
further decreases with increasing GO content. This result cannot
be explained based on the strong hydrogen banding of carboxylic
acid groups from SA and GO, but rather is attributed to the physical
crosslinking of GO with the polysaccharide macromolecules [30] or
to the decrease of relative content of polysaccharides. Further, this
behavior would be beneficial for reducing the drug release under
the physiological conditions in the stomach.
 J. Wang et al. / Colloids and Surfaces B: Biointerfaces 113 (2014) 223–229
Fig. 2. SEM images of neat KGM (a and d), KGM/SA-3 (b and e), and KGM/SA/GO-3 (c and f) hydrogels.
The swelling ratio of most hydrogels at pH 6.8 increases to a
higher extent than that at pH 1.2 with increasing time as shown
in Fig. 3b, except for the neat KGM hydrogels that nearly remains
constant. The swelling ratio of KGM/SA hydrogels increases with
increasing SA content. The swelling ratio of all KGM/SA hydrogels
obviously increases with increasing time (first stage), and then
decreases with further prolonging swelling time (second stage).
The increase in the swelling ratio during the first stage is attributed
to the migration of water into the polymer network driven by
the osmotic pressure [31]. The decrease in the swelling ratio in
the second stage is attributed to the expansion of the SA poly-
mer chains and the breakdown of the COO. . . Ca. . . OOC crosslinks
by PO4 3− anion in the media [27]. The partial dissolution of drug
delivery vehicles is the main reason for the burst release of drugs,
which could be reduced by decreasing the dissolution rate and
avoiding the disintegration of the vehicles. However, the swelling
ratio of KGM/SA/GO hydrogels increases with increasing time. All
KGM/SA/GO hydrogels maintain their original shape. This behav-
ior may be attributed to the physical crosslinking of GO with SA
and KGM macromolecules, that overcomes the disintegration of the
gels. Further, the swelling ratio of KGM/SA/GO hydrogels decreases
with increasing GO content because the interactions between the
polysaccharides and GO strengthen as the content of GO increases.
Thus, the results indicate that KGM/SA/GO hydrogels can prevent
the burst release of drugs.
227
3.3. 5-FU loading
The entrapment efficiencies (EEs) of 5-FU on KGM, KGM/SA-
1, KGM/SA-2, KGM/SA-3, KGM/SA/GO-1, KGM/SA/GO-2, and
KGM/SA/GO-3, as determined by their UV spectra at 265 nm, are
10.29%, 13.32%, 15.50%, 17.49%, 22.73%, 27.09%, and 32.04%, respec-
tively. The results indicate that the more the GO content in the
hydrogels, the more is the 5-FU loading. This shows that the GO is
indeed a promising candidate for drug carrier materials.
3.4. 5-FU release behaviors
The controlled release behaviors of 5-FU from KGM, KGM/SA-
3, and KGM/SA/GO-3 hydrogels at pH 1.2 HBS and pH 6.8 PBS are
shown in Fig. 4a and b, respectively. The neat KGM and KGM/SA-
3 hydrogels were found to release 98.77% and 86.00% of the
entrapped 5-FU during 2 h in pH 1.2 HBS, respectively, whereas
only 32.55% of 5-FU was released from KGM/SA/GO-3 hydrogel
during this time and reached the equilibrium after 6 h (38.02%).
These results show that the prepared KGM/SA/GO-3 hydrogel could
obviously inhibit the release of 5-FU from the hydrogel at low pH.
This behavior may reduce the gastric toxic effects. At pH 6.8 PBS, the
neat KGM and KGM/SA-3 hydrogels release 95.49% and 100% of the
entrapped 5-FU during 2 h, however, only 45.93% of the entrapped
5-FU was released from KGM/SA/GO-3 hydrogel during this time
228 J. Wang et al. / Colloids and Surfaces B: Biointerfaces 113 (2014) 223–229
Fig. 3. The swelling kinetics of different hydrogels at pH 1.2 (a) HBS and 6.8 (b) PBS
at 37 ± 0.5 ◦ C. Each data point represents the mean ± S.D. of three determinations.
and reached the equilibrium after 12 h (84.19%). All the results
indicate that the prepared KGM/SA/GO-3 hydrogel could obviously
delay the release of 5-FU from hydrogel and overcome the burst
release problem of model drugs from traditional polysaccharide
based hydrogels.
Moreover, this result is also in good agreement with the effect
of the pH on the swelling of hydrogels as discussed in Section
3.2 and the surface morphology and structure in Section 3.1.3.
Furthermore, although GO is one-atom thick, it contains many
oxygen-containing functional groups such as hydroxyls, epoxides,
carbonyls, and carboxylic acid groups, that are very suitable for
forming covalent and non-covalent bonds with 5-FU owing to its
good surface activity and solution processability.
More convincing evidence comes from the UV–vis spectroscopic
data (SD Fig. 1 of Supplementary Data). The GO shows a single broad
peak at 230 nm, whereas free 5-FU shows a strong peak at 265 nm.
The interaction between 5-FU and GO is evident from the spectrum
of the GO/5-FU nanohybrid, which clearly shows the characteris-
tic absorption peaks of 5-FU. After forming the nanohybrid, the
absorption peak of 5-FU blue shifted from 265 to 260 nm, and the
absorbance significantly increased. Therefore, GO is shown to be a
good drug-binding effector for controlling the release rate of 5-FU
from KGM/SA/GO-3 hydrogels.
Fig. 4. The controlled release behavior of 5-FU from KGM, KGM/SA-3, and
KGM/SA/GO-3 hydrogels at pH 1.2 (a) HBS and pH 6.8 (b) PBS at 37 ± 0.5 ◦ C. Each
data point represents the mean ± S.D. of three determinations.
Supplementary material related to this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.colsurfb.
2013.09.009.
For the purpose of precisely understanding the release
mechanism, the drug release kinetics data obtained from the
KGM/SA/GO-3 hydrogel were fitted to the following equation pro-
posed by Ritger and Peppas [32] (Eq. (4)) as follows:
Mt
= kt n (4)
M∞
where Mt /M∞ is the fraction of drug released at time t, k is a con-
stant related to the properties of the drug delivery system and n is
the diffusion exponent that characterizes the drug release mecha-
nism. When the value of n is >0.5, it indicates that the drug release
process follows the non-Fickian diffusion mechanism. When the
value of n is <0.5, it indicates that the drug release process follows
the Fickian diffusion mechanism. The values of n calculated accord-
ing to the above method were found to be 0.58 and 0.31 at pH 6.8
and 1.2, respectively. Thus, the KGM/SA/GO-3 hydrogel follows the
Fickian diffusion controlled release mechanism at pH 1.2; whereas
it follows the non-Fickian diffusion controlled mechanism at pH 6.8
follows.
 J. Wang et al. / Colloids and Surfaces B: Biointerfaces 113 (2014) 223–229
4. Conclusions
This study was undertaken to decrease the release rate of drugs
and solve the frequently observed burst release problems from
hydrogel matrices. The novel hydrogels were successfully pre-
pared using graphene oxide (GO) as the drug-binding effector.
The GO nanosheets significantly influenced the micromorphology,
swelling ability, and drug loading. Furthermore, the in vitro release
studies from KGM/SA/GO-3 hydrogels showed that the burst phe-
nomenon could be avoided at the beginning of release tests and
excellent pH sensitive could be achieved. All the results showed that
GO is a good drug-binding effector for controlling the release rate
of drugs and KGM/SA/GO-3 hydrogels could be a suitable polymer
carrier for the site-specific drug delivery in the intestine. Unde-
niably, a lot more systematic explorations are demanded in order
to better understand the in vivo long-term fate and toxicology of
graphene at different doses in various animal models before any
clinical applications of this novel nanomaterial could be pursued.
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