Influence of functionalised multiwalled carbon

nanotubes with imidazole derivative and

thiosemicarbazide on MKN45 and SW742
cancer cells
H. Tahermansouri*1, E. Abedi1, S. Heidari-Keshel2 and A. Tarlani3
Carboxylated multiwall carbon nanotubes (MWCNT-COOH) were first modified by an imidazole
derivative, 2-amino-1-methyl-5-(3,4,5-trimethoxybenzylidene)-1H-imidazol-4(5H)-one, to form a
MWCNT-Im and then by thiosemicarbazide to produce MWCNT-Py. All products were
characterised by Fourier transform infrared spectroscopy, Raman spectroscopy, scanning
electron microscope, energy dispersive X-ray spectroscopy, solubility test, thermogravimetric
analysis, derivative thermogravimetric and cellular investigations. These functionalisations have
been chosen due to active sites of C5C and carbonyl groups in MWCNT-Im and NH2 and sulphur
groups in MWCNT-Py, which might be used as functional materials in future. Toxicity of these
samples was evaluated with human gastric (MKN45) and colon (SW742) cancer cells, and the
killed cell numbers were measured by reduction in living cells with 3-(4,5-dimethyl-2-thiazolyl)2,5-diphenyltetrazolium bromide (MTT) after 48 h of cell culture experiments. Cellular investigations showed high toxicity of modified MWCNTs on the gastric cancer cells compared to colon
cells. In addition, MWCNT-Py sample indicated the highest toxicity for both cancer cells
compared to other samples.
Keywords: Carbon nanotubes, Functionalisation, Imidazole derivative, Cancer cells, Toxicity, MTT

Introduction
Carbon nanotubes (CNTs), as one form of carbon in
which the atoms are arranged in hexagon lattice of
enrolled cylindrical graphitic sheets with diameter of
the order of a nanometre, have attracted great attention
due to their exceptional properties such as unique size
distributions, novel hollow tube structures, high specific
surface areas and electrical semiconductivity and conductivity.1,2 These properties have revealed that CNTs
can be used in many fields such as photocatalysis,3
hydrogen storage, 4 medicine and drug delivery 5,6 and
adsorbent.7,8 In addition, the carbon based materials, in
particular CNTs, are known to interact with polymers
such as nylon 6,6, polyethylene and polypropylene that
commonly improve their structural, physical and biocompatible characteristics.915 The medical and biological

1
Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad
University, Amol, Iran
2
Stem Cell Preparation Unit, Eye Research Center, Farabi Eye Hospital,
Tehran University of Medical Sciences, Tehran, Iran
3
Inorganic Nanostructures and Catalysts Research Laboratory, Chemistry
& Chemical Engineering Research Center of Iran, Pajoohesh Boulevard,
km 17, Karaj Highway, Tehran 14968-13151, Iran

*Corresponding author, email h.tahermansuri@iauamol.ac.ir

2015 W. S. Maney & Son Ltd.

Received 23 October 2014; accepted 5 December 2014
DOI 10.1179/1753555714Y.0000000251

applications of pure CNTs are limited because of their

high hydrophobicity, low functionality and the large size.
Therefore, CNTs must be functionalised with hydrophilic
substituents, such as those containing terminal hydroxyl,
amine or carboxylic groups. Functionalisation is a
chemical process that inserts functional groups on the
sidewall of CNTs. On the other hand, the attached
functional groups to CNTs can be linked to a wide variety
of active molecules, which is a key step for biomedical
applications.1618 Many studies showed which functionalised CNTs could be exploited in applications such as
drug molecules and protein delivery system,19,20 photo
thermal therapy21 and molecular imaging.22 Thus, the
extensive researches have been dedicated to the functionalisation of CNTs, which can be cited oxidation,23
radical addition,24 polymerisation,25 carbanion addition26 and amidation.2732 In addition, review articles
have been presented to this topic.1,33 In this current study,
we have investigated the attachment of an imidazole
derivative, 2-amino-1-methyl-5-(3,4,5-trimethoxybenzylidene)-1H-imidazol-4(5H)-one, to the multiwall carbon
nanotubes (MWCNTs) for producing MWCNT-Im
and then by thiosemicarbazide to form 5-amino-4-methyl3-(3,4,5-trimethoxyphenyl)-3,4 dihydroimidazo [4,5-c] pyrazole-2(1H)-carbothioamide (MWCNT-Py) on the CNTs.

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1 Reaction paths for introduction of imidazole derivative groups on MWCNTs and transformation of these groups to pyrazole derivative groups

In recent years, the annual global production of CNTs

in massive scale caused this nanomaterial mainly exposed
to human and environment.34 On the other hand, the
peculiar properties of CNTs, as mentioned above, allow
their easy transport to the environment and interaction
with cell materials, developing their eventual toxic effects.
Therefore, it is essential to thoroughly investigate the
toxicity and the biocompatibility of CNTs to humans and
the environment. With regard to the toxicity of CNTs,
there is the limited available information for this topic.
The results of the studies have been so far confusing;
some reports show no or very low toxicity of CNTs, 35,36
and some of them show different adverse effects such as
apoptosis37 or decreasing cell proliferation and activity in
a dose dependent manner.38 Taking this background into
account, the purpose of the present work was to study the
cytotoxicity of modified MWCNTs on the cancer cells in
human gastric and colon. The toxicity investigations
showed high toxicity of MWCNT-Py on cancer cells as
compared to other samples.

Experimental
Materials and characterisations
All reagents and solvents [thiosemicarbazide, thionyl
chloride (SOCl2), tetrahydrofuran (THF), dimethyl formamide (DMF), 1,3,5-trimethoxy benzaldehyde and creatinine] from Merck Chemical Inc. and MWCNTs-COOH
(%95 purity, OD: 1020 nm, length: 0?52 mm, Neutrino
Co., Ltd) were purchased and used as received. 2-Amino-1methyl-5-(3,4,5-trimethoxybenzylidene)-1H-imidazol-4 (5H)one is prepared from the reaction of creatinine with 3,4,
5-trimethoxy benzaldehyde.39 Fourier transform infrared
spectroscopy (FTIR) spectrum was recorded using KBr
tablets on a Thermo Nicolet Nexus 870 FTIR spectrometer. Raman spectra recorded on Almega Thermo
Nicolet Dispersive Raman Spectrometer (532 nm of a
Nd:YLF laser). Scanning electron microscopy (SEM)
and energy dispersive X-ray spectroscopy (EDX) were
used to study the morphology and chemical composition
of the MWCNTs respectively. These measurements
were carried out on the VEGA\\TESCAN-LMU Electron Microscope. The samples were investigated by thermogravimetric analysis (TGA; NETZSCH TG 209 F1
Iris) in the N2 (10uC min21).

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Preparation of MWCNT-Im
MWCNT-COOH (200 mg) was suspended in 30 mL of
SOCl2 and 1 mL of DMF. Then, the mixture was stirred at
70uC for 48 h under reflux. Subsequently, the residual
SOCl2 was removed by reduced pressure distillation to
yield the acylchloride functionalised MWCNT (MWCNTCOCl). MWCNT-COCl (150 mg) was mixed with 400 mg
of 2-amino-1-methyl-5-(3,4,5-trimethoxybenzylidene)-1Himidazol-4(5H)-one in 40 mL of DMF, and the reaction
mixture was stirred at 100uC for 96 h. Then, the mixture
was cooled to room temperature, filtered and washed
thoroughly with DMF, ethyl alcohol and THF. Subsequently, the black solid was dried at room temperature
for 8 h under vacuum condition.

Preparation of MWCNT-Py
Eighty milligrams of the MWCNT-Im was sonicated in
30 mL of DMF for 15 min and gave out a homogeneous
suspension. Then, 250 mg of thiosemicarbazide was
added to the reaction mixture and was stirred at 100uC
for 96 h. After cooling to room temperature, the
reaction mixture was separated by centrifugation and
washed thoroughly with DMF, ethyl alcohol and THF.
Thus, the obtained solids were dried by vacuum for 6 h.

Cellular study
The following substances were obtained from the
sources as indicated. Cell culture medium (RPMI1640),
fetal calf serum, 0?25% trypsin with 1 mM methylene
diamine tetra acetate (EDTA), streptomycin sulphate
and penicillin G sodium, all from GIBCO (Grand
Island, NY, USA), were obtained. Human gastric cancer
cell line MKN45 (NCBI no. C615) and human colon
cancer cell line (SW742) were provided by the Iranian
Pastor Institute Cell Bank (Tehran, Iran). MKN-45 or
SW742 was cultured in RPMI 1640 supplemented with
10% fetal bovine serum and 1% L-glutamine, penicillin
and streptomycin. For these experiments, cells were
seeded at a density of 16105 cells mL21 in 96-well
plates. At least three time points are depicted for each
assay.
MTT Viability assay

Cell proliferation was determined by MTT [3-(4,5dimethyl-2-thiazolyl)-2,5-diphenyl-2H-.tetrazolium bromide]

assay for viable cell numbers. The MTT tetrazolium

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2 Spectra (FTIR) (after baseline correction) of modied MWCNTs

compound is reduced by living cells into a coloured

formazan product that is soluble in tissue culture
medium. The quantity of formazan product is directly
proportional to the number of viable cells in the culture.
Cells (SW742: colon cancer cell lines and MKN45: gastric
cancer cell line) grown in 96-well plates at a density of
16104 cells/well were exposed to modified MWCNTs
contain: MWCNT-COOH, MWCNT-Im, MWCNT-Py
and TCPs (control) for 48 h in 100 mg mL21 concentrations. The assays were performed by adding
0?5 mg mL21 in Hanks balanced salt solution (Sigma,
St. Louis, MO, USA) to each well after aspirating the
spent medium and incubating at 37uC for 4 h with
protection from light. Afterward, 200 ml of the DMSO
(stop solution) was added to each well. The resulting
formazan crystals were solubilised in DMSO and
quantified by measuring absorbance at 570 nm (sample)
and 630 nm (reference) with microplate reader (Rayto
RT-6100). The difference in activity between normal and
modified MWCNTs exposure cultures was used as a
cytotoxicity indicator. All measurements were performed
in triplicate, and six independent experiments were
carried out.
Statistical analyses

All data were collected using EXCEL. Graphing and

statistics were performed with SPSS11?5. Continuous
variables were presented as meanSD (xs). Data

were analysed using one-way analysis of variance to

determine the difference among groups. Relative grown
rate (RGR) of cells was calculated using the formula,
RGR5OD of each group/OD of natural group6100%.
To determine the cytotoxic response of the MWCNTs to
cells in culture, six-graded toxicity and other analytic
methods were used.

Results and discussion

Figure 1 illustrates the procedure for functionalisation
of MWCNT-COOH by an imidazole derivative and
thiosemicarbazide. These functionalisations have been
chosen due to active sites of C5C and carbonyl groups
into the MWCNT-Im and NH2 and sulphur groups
into the MWCNT-Py, which might be used as functional materials in future. The functionalised CNTs
were characterised by FTIR, Raman, SEM, EDX,
solubility test, thermo gravimetric analysis (TGA) and
derivative thermogravimetric (DTG). Figure 2 presents
the FTIR spectrum of modified MWCNTs. In
MWCNT-COOH, the peak at 1575 cm21 is assigned
to C5C stretching mode of MWCNT-COOH that
forms the framework of CNTs.27 The appearance of
absorption peaks at 1724(C5O) and 1150 (CO) cm21
in infrared spectra of MWCNT-COOH clearly indicates
carboxylic groups on the MWCNTs. The two bands at
around 28003000 that can be seen in all spectra can be

3 a TGA and b DTG curves of modied MWCNTs in N2 (10uC min21)

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4 Energy dispersive X-ray spectroscopy spectra and SEM images (inset) of functionalised MWCNTs

related to the CH stretching of MWCNTs defects. In

the spectrum of MWCNT-Im, the new peaks at 3000
3100, 1679, 1624 and 1595 cm 21 can be assigned to the
CH aromatic ring, amide group [C(5O)NH linkage],
C5O creatinine and C5C of the imidazole derivative
respectively (as compared to spectrum of MWCNTCOOH), which confirmed the formation of MWCNTIm. In the spectra of MWCNT-Py, the presence of the
remarkable peaks at 1610 and 1124 cm21 can be related
to the NH2 scissoring mode32 and C5S mode,28,31
respectively (as compared to spectrum of MWCNT-Im).
In addition, the peak at 1655 cm21 can be assigned to
the C5N or C5C stretching mode (probably overlapped together) of imidazole ring,29,32,40 which confirmed the functionalisation of MWCNTs with this
compound. The other peaks at around 32003500,
14701600, 13001420 and 12001300 cm21 in the
MWCNT-Im and MWCNT-Py spectra can be corresponded to NH stretching mode, C5C nanotube and
aromatic ring modes, CN and CO stretching modes
respectively. Thus, FTIR spectra confirm that
MWCNT-COOH has been successfully modified by
imidazole derivative and thiosemicarbazide.
Other evidence for bonding of the imidazole derivative to
the surface of MWCNT is provided by TGA that provides

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quantitative information as regards functionalisation of

CNTs. In fact, this thermal defunctionalisation is based on
the observation that the necessary temperature for
elimination of functional groups bound to nanotubes is
considerably lower than for the nanotube itself, enabling in
this way selective removal of the functional groups in a
thermal analysis scan. The TGA plots of MWCNTCOOH, MWCNT-Im and MWCNT-Py are shown in
Fig. 3a. Since MWCNT-COOH is almost thermally stable,
the weight loss before the decomposition of MWCNTCOOH can be used to estimate the quantity of various
groups attached to nanotube by TGA. According to
Fig. 3a, MWCNT-Im sample exhibits one major decomposition at around 202500uC with a weight loss ,11?1%,
which can be assigned to decomposition of the attached
imidazole derivative to MWCNTs (as compared with the
TGA curve of MWCNT-COOH). In contrast, the major
decomposition of MWCNT-Py sample occurred at around
110340uC with a weight loss ,18?2%, which arise from
decomposition of the pyrazole derivative on the CNT
surface. These results indicate that there is one imidazole
derivative for MWCNT-Im per 180?5 and one pyrazole
derivative for MWCNT-Py per 125?8 carbon atoms of
MWCNTs respectively at 500uC. The DTG curve provides
further evidence for covalent modification of MWCNTs

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5 Raman spectra of modied MWCNTs; baseline was corrected for luminescence background

(Fig. 3b). This curve can be used to determine the

decomposition temperature of the CNT, which is the
temperature at the highest peak for the CNTs on the DTG
curve, as well as defining the mass loss event as a single
decomposing species (e.g. single peak) or as multiple decomposition events (e.g. double peaks, shouldered peaks).
According to Fig. 3b, the one major peak at 363uC could
be attributed to the loss of the imidazole derivative bonded

6 Photographs of dispersions of (1) MWCNT-COOH and

(2) MWCNT-Py in DMF after standing for 3 days; samples are sonicated for 20 min, and photographs were
taken 3 days after putting bottles on table (value of
MWCNTs: 5 mg)

to MWCNT.27 On the other hand, DTG curve of

MWCNT-Py shows one peak at 248uC, which can be
assigned to the loss pyrazole derivative. Overall, these results
successfully confirm the functionalisation of MWCNTCOOH with these compounds.
The EDX spectra bestead to understand the chemical
composition of MWCNTs before and after functionalisation and together with SEM images determine
the presence of the imidazole derivative and thiosemicarbazide groups on the MWCNTs. As can be seen
from Fig. 4, the EDX spectrum of MWCNT-Im
and MWCNT-Py shows that except from carbon and
oxygen, nitrogen are detected as 2?49 and 6?15 wt-%
respectively (as compared to EDX of MWCNTCOOH). The presence of sulphur (3?15 wt-%) in EDX
of MWCNT-Py, which can be attributed to the presence
of the attached pyrazole derivative to MWCNTs,
confirmed this functionalisation. In addition, SEM
images of MWCNT-Im and MWCNT-Py show that
the thickness of their surfaces slightly increased after the
functionalisation process (as compared to image of
MWCNT-COOH), which may be due to covalently
bonded organic compounds on the surface of MWCNTs.
The Raman spectra of modified MWCNTs are shown
in Fig. 5. All of the spectra have the same pattern, which
implies these reactions do not effect on the graphite
structure of the MWCNTs.26 According to Fig. 5, the D
and G bands of the modified MWCNTs at ,1350 and
1580 cm21, which originate from the defects and disorder

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7 Growth of MKN45 and SW742 cancer cells on samples

8 MTT assay for TCPS and modied MWCNTs after 48 h; concentration of samples was considered similar
(100 mg mL21)

induced peaks and the in plane tangential stretching mode

of carboncarbon bonds respectively, can be clearly observed
for the three different MWCNTs.41 Furthermore, the D and
G band intensity ratio (ID/IG) of the three samples, which are
1?14 for MWCNT-COOH, 1?15 for MWCNT-Im and 1?17
for MWCNT-Py, showed that these reactions have improved
the degree of disorder.
The dispersion test is a fair idea for the functionalisation of
MWCNTs because it shows which the modification on the
MWCNTs has been achieved or not. Figure 6 presents the
dispersed photographs of MWCNT-COOH (1) and
MWCNT-Py (2) in DMF in which the samples sonicated
and stored respectively. As can be seen from Fig. 6,
MWCNT-COOH was insoluble in DMF, while the
MWCNT-Py can be dispersed in DMF homogeneously
and no precipitation was found even after it was sealed for
3 days at room temperature. These results indicate which
MWCNT-COOH was functionalised by pyrazole derivative.
The effect of functionalised MWCNTs on toxicity of
gastric and colon cancer cell lines was investigated. In
this study, the used biological data revealed anticancer
activity against MKN-45 and SW742. Figure 7 shows
images of cell culture on the modified MWCNTs and
control. The images of control samples related to the
culture of cancerous cells on the tissue culture polystyrene (TCPS) surface, which show the cells of well
adhesion and proliferation on the TCPS surface. In
addition, these images indicate effect of the gastric
and colon cancerous cells in the vicinity of modified

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MWCNTs and the control sample in which the modified

MWCNTs well diffuse into and on cancerous cells. Figure 8
shows an MTT assay for TCPS (control) and modified
MWCNTs on the cancer cells. According to Fig. 8, the
toxicity of MWCNT-COOH, MWCNT-Im and MWCNTPy for MKN45 cells obtained 69, 60?4 and 82?6%
respectively. In addition, these values with SW742 cells are
obtained 64?1% for MWCNT-COOH, 48?6% for
MWCNT-Im and 72?2% for MWCNT-Py. This indicates
the toxicity of MWCNT-Py in MKN-45 and SW742 is
more than MWCNT-COOH and MWCNT-Im. In other
words, the effect of pyrazole derivative in killing cancer cells
by MWCNT-Py was more than carboxyl and the imidazole
derivative groups. Overall, the results showed high toxicity
of modified MWCNTs for MKN-45 (about 6982%)
compared to SW742 (about 4872%). So, the functionalisation of MWCNTs by these groups is very influential in
increasing the toxicity of MWCNTs that can be used for
conjugate to drugs of anticancer or biochemically materials.

Conclusions
We have firstly introduced the imidazole and pyrazole
derivative groups on the surface of MWCNTs, MWCNTIm and MWCNT-Py respectively. The obtained results
from analysis of FTIR, Raman, solubility test, SEM,
EDX, TGA and DTG confirmed the formation of
MWCNT-Im and MWCNT-Py. Cellular investigations
showed that MWCNT-Py is a more toxic agent compared

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with other samples for MKN-45 (82?6%) and SW742

(72?2%) cancer cells.

Acknowledgement
The financial and encouragement support was provided
by Research vice Presidency of Ayatollah Amoli branch,
Islamic Azad University.

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Materials Technology: Advanced Performance Materials

2015

VOL

30

NO

229