Green Process Synth 2016; 5: 511–520

Thi Bich Tram Nguyen, Le Hang Dang, Thi Thanh Thuy Nguyen, Dai Lam Tran, Dai Hai Nguyen,
Van Toan Nguyen, Cuu Khoa Nguyen, Thi Hiep Nguyen, Van Thu Le and Ngoc Quyen Tran*

Green processing of thermosensitive

nanocurcumin-encapsulated chitosan hydrogel
towards biomedical application
DOI 10.1515/gps-2016-0062 for this system can be conveniently modulated as trans-
Received May 23, 2016; accepted August 30, 2016; previously dermal drug delivery.
­published online November 1, 2016
Keywords: biomedical application; chitosan; nanocur-
Abstract: In this study, in order to enhance the aque- cumin; thermosensitive copolymer.
ous solubility and to overcome the limitation of cur-
cumin (Cur) in free form, as well as to develop a carrier
for transdermal delivery of hydrophobic pharmaceuti-
cal agents such as Cur, a sonicated synthetic process of 1 Introduction
nanocurcumin (nCur) in thermally responsive Chitosan-
g-Pluronic (CP) copolymer is disclosed herein. The use of Curcumin (Cur; 1,7-bis (4-hydroxy-3-methoxyphenyl)-
CP copolymer solution as a dispersant medium is a very 1,6-hepadiene-3,5-dione) is a yellow lipid-soluble
attractive method to avoid the use of toxic organic sol- natural pigment extracted from the rhizome of turmeric.
vent and non-biocompatible surfactant. The obtained Cur The molecule has exhibited several pharmacological
nanoparticles had a fairly narrow distribution of 8–23 nm. activities such as antioxidant, antiinflammatory [1–3],
nCur-dispersed CP solution showed good stability with no antiseptic [4], anti-Alzheimer’s disease [5], anti-cystic
change in color characteristic and no phase separation fibrosis [6], and wound-healing effects [7]. In addition,
after 1 month of storage. Rheological characterization of clinical trial studies in animals and humans have not
CP hydrogels had indicated sol-gel transition at the same shown any toxicity or side effects of Cur [8, 9]. Paradoxi-
temperature (35°C). Interestingly, the rate of Cur release cally, the therapeutic efficacy of Cur is still limited due
to its poor solubility resulting in a low bioavailability.
Another problem is that Cur undergoes pH-dependent
degradation, or quickly decomposes under alkaline
*Corresponding author: Ngoc Quyen Tran, Institute of Applied
Materials Science, Vietnam Academy of Science and Technology, solution resulting in the formation of 6-(4’-hydroxy-
Ho Chi Minh City, 700000, Vietnam, 3’-methoxyphenyl)-2,4-dioxo-5-hexenal, anillin, and
e-mail: [email protected] ferulic acid [10], which can lead to various health
Thi Bich Tram Nguyen: Department of Natural Science, Thu Dau Mot problems [11]. The poor water solubility and stability
University, Binh Dương, 590000, Vietnam
of Cur thus offer more attempts to enhance its clinical
Le Hang Dang: Institute of Applied Materials Science, Vietnam
Academy of Science and Technology, Ho Chi Minh City, 700000,
relevance.
Vietnam; and School of Biotechnology, International University, Viet A numerous formulation of Cur nanoparticles based
Nam National University in HCMC, 700000, Vietnam on nanosized delivery systems such as liposomes [12],
Thi Thanh Thuy Nguyen, Dai Hai Nguyen and Cuu Khoa Nguyen: polymeric nanoparticles [13], phospholipid complexes,
Institute of Applied Materials Science, Vietnam Academy of Science or micelles [14] have demonstrated high sustained and
and Technology, Ho Chi Minh City, 700000, Vietnam
efficient Cur delivery. In order to increase the effective-
Dai Lam Tran: Vietnam Graduate University of Science and
Technology, Vietnam Academy of Science and Technology, Ha Noi, ness, co-solvents or anionic/non-anionic surfactants are
100000, Vietnam also added [15]. These used in previous studies, however,
Van Toan Nguyen: Department of Chemistry and Food Technology, required several complicated purification steps during
Ba Ria-Vung Tau University, Vung Tau City, 740000, Vietnam production to remove the side effect caused by the
Thi Hiep Nguyen: Biomedical Engineering Department,
remains of these surfactants [16, 17]. Colloidal solutions
International University, Viet Nam National University in HCMC,
700000, Vietnam
of surfactants that form micelles or vesicles are currently
Van Thu Le: Institute of Chemistry-Biology and Professional being developed, which can solve the remaining problem
Documents, Ministry of Public Security, Ha Noi, 100000, Vietnam of these aforementioned methods.
512      T.B.T. Nguyen et al.: Green processing of thermosensitive nanocurcumin-encapsulated chitosan hydrogel

Pluronic F127 (F127), an amphiphilic block copoly- 2.2 Synthesis of the CP copolymer
mer, is known to form spherical micelles in solution, so
F127 has been well-utilized as a nanoplatform for drug The synthesis of CP copolymers is presented in Scheme  1. Briefly,
delivery. These micelles have high solubilizing capac- F127 (1 mmol) was firstly activated at two hydroxyl terminals at 70°C
ity and rather low critical micelles concentration value with a coupling agent (p-nitrophenyl chloroformate) in a free solvent
reactor. After 6 h, the mixture was cooled to room temperature. Etha-
that makes them stable in vivo, resulting in a good ability
nol was added to the mixture and the solution was dialyzed in diethyl
carrier for hydrophobic and sparingly soluble pharma- ether following precipitation to obtain NPC-activated F127. A diluted
ceuticals [18]. However, F127 shares some biological dis- aqueous solution of 3-amino-1-propanol (1.2 mmol) was slowly added
advantages, including low cell adhesion [19] and inability into an ethanol solution of the activated F127 in order to obtain an
to be enzymatically degraded [20]. To overcome the draw- NPC-F127-OH product. CS was initially dissolved in HCl solution at
pH ~ 3.0 and then adjusted to pH ~ 5.0. The NPC-F127-OH solution was
backs of F127 gels, F127 was grafted onto other biologi-
added dropwise into the prepared CS solution under stirring. In this
cal polymers [21, 22]. In this study, the thermosensitive study, the concentration of CS was fixed while the concentration of
grafted Chitosan-g-Pluronic (CP) copolymer was prepared F127 was varied from 1% wt/v to 20% wt/v. The resultant solution
and used as a dispersant for synthesizing Cur nanoparti- was dialyzed against DI water with dialysis membrane (MWCO: 14
cles. Incorporation of the released Cur and the copolymer kD) for 1 week before freeze drying to obtain a CP copolymer (as
could perform potential of the injectable composite hydro- Scheme 1). The products were stored in the refrigerator for further
study. All products of each step were determined by proton nuclear
gel for biomedical administration.
magnetic resonance (1H-NMR) (Varian 400 spectrometer; Varian,
USA) and Fourier transform infrared (FTIR) spectroscopy (Nicolet
5700; Thermo Electron Corporation, MA, USA).
2 Materials and methods
2.1 Materials 2.3 Thermal behavior of CP hydrogel

Chitosan (CS; 100–300 kD, 95% deacetylation), Cur, p-nitrophenyl The thermosensitive property of copolymer was obtained by the tube
chloroformate (NPC) and amino-1-propanol Pluronic F127 were pur- inversion method, which was used previously by several groups
chased from Acros Organics (Geel, Belgium) and diethyl ether was to determine the gel boundary of gel-sol behavior [23]. In the tube
purchased from Sigma (St. Louis, USA). Dialysis membrane (MWCO: inversion method, 3  ml vials with different amount of copolymer
14 kD) was supplied from Spectrum Labs (California, USA). Other sol- (5% wt/ml, 8% wt/ml, 10% wt/ml, 12% wt/ml, 15% wt/ml, and 20%
vents were used without further purification. wt/ml) were dissolved in DI water and kept at 4°C in 24 h before the

Scheme 1: A synthetic process of thermosensitive CP copolymer.

 T.B.T. Nguyen et al.: Green processing of thermosensitive nanocurcumin-encapsulated chitosan hydrogel      513

examination. All vials were then tested at different temperature

points (4°C, 25°C, 30°C, 37°C, 45°C and 50°C) and inverted to observe
sol/gel behavior.

2.4 Rheological study

The rheology study was conducted on a rheometer (HAAKE

­RheoStress 6000; Thermo Scientific, MA, USA) which followed Pham
Trong et al. [24]. Briefly, a 2–3 ml sample which was used in the tube
inversion method was used for measurement. The oscillatory tem-
perature program was set up for determining the characterization of
CP hydrogel at a temperature range of 4–60°C within the constant
rates of ± 0.1°C/min.

2.5 Preparation of nanocurcumin-loaded CP hydrogel

The Cur in absolute ethanol was added drop-wise into the CP solution
under an ultrasonication process. Further ethanol solvent was evap-
orated by the rotary evaporator to obtain a homogeneous nanocur-
cumin (nCur)-loaded CP solution. Morphology of Cur nanoparticles
was observed by transmission electron microscopy (JEM-1400 JEOL)
at 25°C. Spectral analysis was observed by UV-visible spectroscopy
(Agilent 8453 UV-visible spectrophotometer) at 420  nm wavelength
[25]. The pure Cur was prepared in absolute ethanol in the concentra-
tion range 1–10 µg/ml so as to set up a standard curve.

2.6 In vitro release kinetics of nCur

An in vitro release study, a diffusion method with a dialysis mem- Figure 1: Fourier transform infrared (FTIR) spectra of the activated
brane, was used to investigate the in vitro release of Cur from the F127 (NPC-F127-NPC and NPC-F127-OH) and CP copolymer.
nCur-loaded composite hydrogel. The dialysis bag (MWCO 14 kDa)
containing a 2  ml sample was suspended in 10  ml phosphate-buff-
ered saline (PBS) which had been maintained over a period of 24 h prepared using an activated Pluronic F127 to graft onto CS
at 37°C ± 0.5°C in a water bath. At selected time intervals (0 h, 0.25 h, via the formation of covalent carbamate linkages. The FTIR
0.5 h, 1–6 h), 1.5 ml of sample was collected and replaced by an equal spectrum of CS shows two peaks at 1642 cm−1 and 1664 cm−1
volume of fresh medium. The Cur content was quantified by the afore-
as a result of the strong N-H bending in the primary amine
mentioned Agilent 8453 UV-visible spectrophotometer. The release
experiments were performed in triplicate with 95% confidence inter- (-NH2) groups and the amide I (C=O stretching) and amide
vals. The cumulative release of drug was performed from Eq. 1 [26]: II (weaker N-H bending than that in the primary amine
n− 1 in the residual (5%) acetylated amine (-NH-(C=O)-CH3)
Q = Cn Vs + Vt ∑ C n − 1 (1)
groups of CS [27–29]. In the spectrum of CP, however, the
i= 1

amide II peak at 1642 cm−1 is barely identifiable, while the
where: Q = cumulative release (mg/ml), Cn = concentration at time t,
n− 1
amide I peak at 1664 cm−1 is apparent. The diminished
Vs = volume of PBS medium, Vt = volume of sample, and ∑C n−1
amide II peak is presumably due to the loss of primary
= Sum of concentrations of Cur i = 1 (µg/ml) determined at sampling
intervals 1 through n – 1. amine (-NH2) groups to the secondary (-NH-) ones when
CS is linked with the activated F127, which at the same
time strengthens the amide I peak as a result of the forma-

3 Results and discussion tion of more amide bonds. The formation of NPC-F127-NPC
by activation both terminal hydroxyl groups with p-NPC
is confirmed throughout 1H-NMR spectra (the spectra are
3.1 C
 haracterization of CP copolymer not shown). 1H NMR spectrum of the activated F127 shows
a prominent resonance peak at δ = 4.42 ppm that is char-
FTIR spectroscopy (Figure 1) and 1H NMR (Figure 2) show acteristic of the terminal methylene protons (-CH2-CH2-) in
that the thermosensitive copolymer was successfully the activated F127, along with the major resonance peaks
514      T.B.T. Nguyen et al.: Green processing of thermosensitive nanocurcumin-encapsulated chitosan hydrogel

Figure 2: Proton nuclear magnetic resonance (1H-NMR) spectra of CP copolymer in D2O.

of F127 at δ = 1.08  ppm and δ = 3.2–3.8 ppm. In addition,

the resonance peaks at δ = 7.38 ppm and 8.22 ppm corre-
sponded to protons on the aromatic group of NPC. By inte-
grating the proton resonance peaks of NPC (δ = 7.38 ppm)
and F127 (δ = 1.08 ppm), the yield of NPC-F127-NPC was
93.27% (1H NMR).
The 1H-NMR spectra of OH-F127-NPC is almost iden-
tical with that of NPC-F127-NPC. The spectrum of OH-
F127-NPC had a presentation of peaks (δ ~ 1.75–2.35 ppm)
corresponding to protons of CH2 groups on the grafted
alkyl moiety. Also, only 59.58% activated Pluronic with
NPC remained, providing evidence of the formation of
NPC-F127-OH.
In Figure 2, the remaining terminal NPC group on
NPC-F127-OH reacted with primary amine groups in CS
to form urethane linkage in the CP copolymer. As shown
in Figure 2, comparison with 1H-NMR of NPC-F127-NPC,
beside the complete disappearance of the two resonance
peaks at δ = 7.38 ppm and 8.22 ppm which is presented for
NPC groups and the major peaks of F127, the 1H-NMR spec-
trum also showed the appearance of resonance peaks at Figure 3: Phage diagram showed thermal behavior of sample
δ ~ 2.0 ppm (peak d) and 2.7 ppm (peak c) (methyl proton with various temperatures (4°C, 25°C, 30°C, 37°C, 45°C and 50°C).
F1-F8:CP hydrogel with various amounts (wt/wt) of F127 and con-
and proton H2, respectively) of CS interrelated to the
stant amount of chitosan (CS).
attendance of CS in the sample.

CP hydrogel showed liquid-like behavior; interestingly,

3.2 Thermoreversible behavior almost all samples, except sample F1 (ratio CS:F127 = 1:1),
became opaque and solid-like on raising the temperature
In the inverted tube method, CP hydrogel demonstrated (T  ≥  25°C). Table 1 shows the preparations in order to get
thermo-responsive behavior via the transition of the the critical concentrations. It is believed that as the content
sol-gel process following the change of temperature of F127 in the sample increased, the gelation temperature
(Figure 3A and Table 1). At lower temperatures (T < 25°C), was down. In other words, a thermo-responsive behavior
 T.B.T. Nguyen et al.: Green processing of thermosensitive nanocurcumin-encapsulated chitosan hydrogel      515

Table 1: The sol-gel behavior of numerous CP copolymers in various test temperature range and their gel temperature.

Sample  CS (g)  F127 (g)  4°C  25°C  33°C  37°C  40°C  50°C  Sol-gel transition  Gelation temperature

F1   1  1  –  –  –  –  –  –  –   N/A
F2   1  2  –  –  –  –  +  +  Yes   N/A
F3   1  3  –  –  –  +  +  +  Yes   N/A
F4   1  4  –  –  –  +  +  +  Yes   N/A
F5   1  5  –  –  +  ++  ++  ++  Yes   N/A
F6   1  10  –  –  ++  ++  ++  +++  Yes   > 37°C
F7   1  15  –  –  +++  +++  +++  +++  Yes   35°C
F8   1  20  –  ++  +++  +++  +++  +++  Yes   25°C

–, No phenomenon.
+, Copolymer solution become high viscosity, slow to flow in the vial.
++, Weak gel, hard to flow in the vial.
+++, Solid-like behavior, non-free flowing in the vial.
N/A, Unidentified.

of CP hydrogel originated from the thermal property of in the aqueous solution. The hydrophobic interactions of
F127. In this study, F127 was grafted on the CS backbone PPO groups and dehydrated CS are suggested to be the
in order to reduce the lower critical solution temperature main force driving the formation of CP hydrogel. In this
of F127 itself at the same concentration, thus the required study, approximately 15% of CP copolymer in the ratio 1:15
concentration of F127 for gel formation is reduced was required to obtain CP hydrogel formulation with the
(< 20  wt%). CP copolymer solution containing less than transition temperature of approximately 37°C.
10% by weight did not form gels over the test temperature To confirm the thermo-responsive behavior of CP
range, while a CP copolymer concentration higher than copolymer, rheological experiments including oscil-
20% by weight led to gel formed in short time (approxi- lation temperature sweep, were used to investigate
mately 25°C) and difficulty in administration. At lower exactly the temperature that the sol-gel transition
temperatures, CP copolymer persists in the monomer state occurs (Figure  4A and  B). Rheology analysis presented
or solution phase. When the temperature is raised, hydro- the change of storage modulus, G’, loss modulus, G’’
phobic interactions take place between PPO groups on during a temperature ramp from 4°C to 45°C under
F127, leading to CP aggregates, and the gelation stages of control shear. At low temperature, G’’ >> G, the angle
CP copolymer are formed by packing of these aggregates 45° < δ < 90° and the phase angle between G’ and G’’ (tan

Figure 4: Rheology of sample (F7, CS:F127 = 1:15) at 15% (A) and 20% (B), providing the evident for thermoreversible property of CP
hydrogel.
516      T.B.T. Nguyen et al.: Green processing of thermosensitive nanocurcumin-encapsulated chitosan hydrogel

δ) >> 1; the sample, therefore, remained as viscoelastic elastic component to the viscous one, with loss tangent
liquid in behavior. At a concentration of 15% wt, both values between 0.5 and 110.
lines of G’ and G’’ raised up instantaneously in the range
30.5–35°C, but G’ increased faster than G’’ while tan δ fell
down. At 35°C, G’ ~ G’’ (G’ = 501.992 Pa and G’’ = 502.125) 3.3 C
 haracterization of nCur in
and tan δ ~ 1 indicated the point of sol-gel transition ­thermosensitive hydrogel
(Figure 4A). However, at a concentration 20% wt, the
sol-gel transition occurred in a narrow range of tempera- nCur was prepared by the wet method in absolute ethanol
ture (20–24.5°C) resulting in greater difficulty in medical instead of using dichloromethane conventionally. Cur
application (Figure 4B). In the plot of the loss tangent ethanol solution was added dropwise into CP copolymer
against temperature (Figure  5), both concentrations solution. In this work, 1:15 of the CS:F127 copolymer weight
under study exhibited the transition from predominant ratio in feed was chosen for future application and charac-
terized in detail. The optimized ultrasonication was found
at 15 min with energy 40% and duty cycle 35%. Prolonged
ultrasonication or increased energy did not improve this
result as noted previously [30].
Transmission electron microscopy (Figure 6) analy-
sis of the resulting particles showed that nCur-loaded was
spherical in shape and existed in the size range of ~8–23
nm. The appearance of blank CP solution (left), and nCur-
loaded CP solution (right) and their sol-gel behaviors are
presented in Figure 7. The vial containing nCur-loaded CP
solution is a transparent yellow, implying good dispersion
in aqueous solution. Interestingly, there was no difference
between the blank CP hydrogel and CP hydrogel with nano-
curmin about the gel temperature (Figure 8). After loading,
the hydrogel composite system also presents Tgel at near
35°C and the nCur could be stable in this system. Conse-
quently, the synthesis of nCur using CP copolymer could
result in a homogenous and stable dosage form in aqueous
Figure 5: Loss tangent of sample F7 at 15 wt % and 20 wt % gel with
media for Cur transdermal delivery.
temperature sweeps.

3.4 In vitro release study

In order to prove the ability of CP of Cur released from the

hydrogel, an in vitro release study was performed using
a diffusion method with a dialysis membrane. Figure  9
demonstrates that the sample was able to slightly release
its loaded drug over a period of time. After 2  h interval,
56.98 ± 0.001% nCur was released from this system. From
2 to 6  h interval, nCur was released at a constant rate.
According to several reports, CS based hydrogels exhibited
their great swelling behavior in the physiological medium;
thus, allows the diffusion of the drug through hydrogel
matrices [31, 32]. Thus, this controlled release of Cur from
the Cur-loaded CP copolymer revealed that the system
Figure 6: Transmission electron microscopy (TEM) of nanocurcumin could be good for application of topical administration in
(nCur) at scale 50 nm. order to treat skin diseases such as wound healing.
 T.B.T. Nguyen et al.: Green processing of thermosensitive nanocurcumin-encapsulated chitosan hydrogel      517

Figure 7: Appearance of blank CP copolymer and nanocurcumin (nCur)-loaded thermosensitive copolymer at 20°C (top) and 37°C (bottom),
respectively.

Figure 9: In vitro release behavior of nanocurcumin (nCur) incor-

porated in CP hydrogel (F127:CS = 15:1) using a diffusion method
Figure 8: Rheology of nanocurcumin (nCur)-loaded CP hydrogel with dialysis membrane method in phosphate-buffered saline (PBS)
(CS:F127 = 1:15) shows Tgel at 34.9°C. (pH = 7.4) at 37 ± 0.5°C as medium.
518      T.B.T. Nguyen et al.: Green processing of thermosensitive nanocurcumin-encapsulated chitosan hydrogel

4 Conclusion [13] Safavy A, Raisch KP, Mantena S, Sanford LL, Sham SW, Krishna
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 T.B.T. Nguyen et al.: Green processing of thermosensitive nanocurcumin-encapsulated chitosan hydrogel      519

Le Hang Dang Dai Hai Nguyen

Dai Hai Nguyen obtained his PhD degree at Ajou University, Republic
Le Hang Dang got her BSc degree from International University, Viet of Korea in 2013. Currently, he works as a researcher at the Institute
Nam National University, Ho Chi Minh City in 2015. She is currently of Applied Materials Science, Vietnam Academy of Science and
a researcher at the Institute of Applied Materials Science, Vietnam Technology. He is also an invited lecturer at TraVinh University and
Academy of Science, Vietnam. Her study focusses on biomedicinal Ho Chi Minh City University of Natural Sciences.
science.
Van Toan Nguyen
Thi Thanh Thuy Nguyen

Van Toan Nguyen got a chemical engineering degree from Ha Noi

Thi Thanh Thuy Nguyen got her PhD in France (2014). She is
University of Technology (2006). He is currently a lecturer at Ba
currently a researcher at Institute of Applied Materials Science,
Ria-Vung Tau University. His teaching and study areas are chemical
Vietnam Academy of Science and Technology. She is also an invited
engineering and biomaterials for biomedical applications.
lecturer in TraVinh University and Lac Hong University. Her teaching
and study areas are pharmaceutical chemistry and biomaterials for
Cuu Khoa Nguyen
biomedical applications.

Dai Lam Tran

Cuu Khoa Nguyen obtained his PhD degree in Russia. Currently, he

is the director of the Institute of Applied Materials Science (VAST).
He is also an invited lecturer at TraVinh University, Can Tho Univer-
Dai Lam Tran graduated from Belorussian State University (in the sity and Lac Hong University. His teaching and study areas are phar-
former USSR) with a Master’s degree in Solid State Chemistry maceutical chemistry and biomaterials for biomedical applications.
(1994). He received his PhD in Physical Chemistry (Surface-Interface)
from the University of Paris VII, Paris, France, in 2003. He was a
lecturer at Hanoi University of Technology from 1998 to 2008. He
has been an associate professor at IMS since 2009. His research
focusses on nanofabrications, characterizations and applications of
nanobiomaterials in drug delivery systems and biosensors.
520      T.B.T. Nguyen et al.: Green processing of thermosensitive nanocurcumin-encapsulated chitosan hydrogel

Thi Hiep Nguyen Ngoc Quyen Tran

Ngoc Quyen Tran got his PhD in Republic of Korea in 2011. He is

Thi Hiep Nguyen got her PhD from the Department of Biomedical currently a researcher at the Institute of Applied Materials Science,
Engineering and Materials, SoonChunHyang University, Korea. Cur- Vietnam Academy of Science and Technology and Institute of
rently, she is a lecturer at Department of Biomedical Engineering, Research and Development, Duy Tan University, Da Nang City,
International University, Vietnam National University, Ho Chi Minh Vietnam. He is also an invited lecturer at TraVinh University and Lac
City. Her teaching and study areas are biomaterials for biomedical Hong University. His teaching and study areas are biochemistry and
applications. biomaterials for biomedical applications.

Van Thu Le

Van Thu Le worked as a researcher at the Institute of Chemistry-

Biology and Professional Documents, Ministry of Public Security.
He received his PhD in Physiochemical-Theoretical Chemistry from
VietNam Academy of Science and Technology. Nearly 60 of his
articles and reports related to polymer composite and nanocompos-
ites have been published in national and international journals. His
present research concerns nanocomposites and polymer composite
materials.