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Ultrasonic-assisted synthesis of magnetite

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DOI: 10.1016/j.matchemphys.2011.04.083

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Materials Chemistry and Physics

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

Ultrasonic-assisted synthesis of magnetite based MRI contrast agent using

cysteine as the biocapping coating
Reza Ahmadi a, , Mahrooz Malek b , Hamid Reza Madaah Hosseini a , Mohammad Ali Shokrgozar c ,
Mohammad Ali Oghabian d , Afshin Masoudi a , Ning Gu e , Yu Zhang e
a
Department of Materials Science and Engineering, Sharif University of Technology, P.O. Box 11155-9466, Tehran, Iran
b
Medical Image Centre, Imam Khomeini Hospital, Tehran Medical University, Tehran, Iran
c
National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran
d
Research Centre for Sciences and Technology in Medicine, Tehran University of Medical Sciences, Tehran, Iran
e
Jiangsu Key Laboratory of Biomaterials and Devices, Nanjing, China

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

Article history: Magnetite nanoparticles (mean particle size ranging from 10 to 20 nm) were prepared by a biomolecule-
Received 23 September 2010 assisted solution-phase approach under ultrasonic irradiation. Cysteine was used as the capping agent
Received in revised form 15 February 2011 in the solution. The results show that cysteine could be an efcient biocapping agent in producing Fe3 O4
Accepted 27 April 2011
nanoparticles. The crystal structure and magnetic properties of the nanoparticles were characterized
by XRD and VSM techniques, respectively. FT-IR was used to investigate the presence of cysteine on the
Keywords:
nanoparticles surface. The inuence of pH value of the solution on the size distribution and hydrodynamic
Magnetic materials
size of nanoparticles were studied by TEM and DLS methods, respectively. The MTT assay performed by
Nanostructures
Electron microscopy
incubation of L929 cells, showed the good biocompability of synthesized ferrouids. In vitro T1 and T2
Fourier transform infrared spectroscopy relaxivity measurements along with in vivo studies, which were conducted on rats, demonstrate that
(FT-IR) synthesized nanoparticles are applicable as the contrast agents, especially for imaging of the lymphatic
system.
2011 Elsevier B.V. All rights reserved.

1. Introduction used for preparation of magnetite nanoparticles [15,16]. In this

Magnetite nanoparticles have drawn enormous attention due to
the wide range of applications such as drug delivery [1], MRI con-
trast agent [2], separation of the biomolecules [3], cancer therapy
[4], electrophotographic developer [5] and data storage technology
[6]. Many methods have been developed for the synthesis of the
magnetite nanoparticles with different morphologies and size dis-
tribution such as template method [7], microwave irradiation [8,9],
solgel method [10], hydrothermal method [11,12] and thermal
decomposition [13,14]. Some researchers used thermal decompo-
sition method to produce monodisperse magnetite nanoparticles
with the mean particle size less than 10 nm. These particles were
functionalized with thermosensitive polymers such as chitosan-
g-poly (N-isopropylacrylamide-co-N,N-dimethylacrylamide)
[13] and dextran-g-poly (N-isopropylacrylamide-co-N,N-
dimethylacrylamide) [14] to increase the drug-loading ability
and control the drug release.
Recently, co-precipitation from the solution of ferrous/ferric
mixed salt solution in the alkaline medium has become widely
Corresponding author. Tel.: +989126272374.
approach, nanoparticles tend to agglomerate due to the high spe-
cic surface area, surface energy and magnetization. One of the
conventional approaches to improve the size distribution and
morphology of magnetite nanoparticles without any consider-
able agglomeration is peptizing magnetite in acidic media such
as HClO4 [17]. In this approach, particles agglomeration decreases
due to their similar surface charge. Another way is coating of the
magnetite nanoparticles with a capping agent. Two critical param-
eters in choosing the capping agent are chemical complementarity
and structural compatibility. Amino acids, which have good com-
patibility with biological materials, have been used as capping
agents to control size distribution and prevent the agglomeration
of nanoparticles [18,19]. Among all the amino acids, cysteine with
three functional groups has a certain binding afnity to the metal
atoms, which may control the size and the morphology of mag-
netite nanoparticles without any agglomeration. This surfactant
has not been employed as biocapping agent for synthesizing MRI
contrast agent yet, but has been used in similar biological appli-
cations [20,21], conrming the biocompatibility of cysteine as a
biocapping agent.
Another strategy to decrease particles agglomeration and to
improve the size distribution and morphology of nanoparticles

0254-0584/$ see front matter 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.matchemphys.2011.04.083

Please cite this article in press as: R. Ahmadi, et al., Ultrasonic-assisted synthesis of magnetite based MRI contrast agent using cysteine as the
biocapping coating. Mater. Chem. Phys. (2011), doi:10.1016/j.matchemphys.2011.04.083
 ARTICLE IN PRESS
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Fig. 1. Detailed experimental owchart of Fe3O4 nanoparticles preparation.
is the synthesis of magnetite nanoparticles under ultrasonic irra-
diation. Ultrasonic-assisted synthesis of nanoparticles can reduce
particles agglomeration to some extent due to the steady nature of
stirring by the ultrasonic waves. So far, ultrasonic irradiation has
been recognized as an efcient technique in synthesis of various
kinds of organic and inorganic materials [22,23].
In the present study, the effects of two important process param-
eters the sequence of adding reactants to the reactor and the
way in which surfactant was added to the solution were inves-
tigated. In the majority of earlier processes [24,25] the alkaline
agent (e.g. NaOH) is added gradually into the acidic solution of
iron salts and pH is varied from an acidic range to alkaline one
(e.g. from 3 to 13). This can result in the formation of particles
in a wide range of pH and consequently a wide range of parti-
cle size. On the other hand, in some reported works [26,27], the
alkaline solution is added suddenly into the iron source solution.
In the present study, the salt solution was added into the alka-
line reactant thus, the pH variation was little and limited in the
alkaline range. Besides, in most cases [2427] surfactant is added
after the particles formation. New approach which is used in this
research in order to reduce the particle size, narrow the particle
size distribution and prevent the agglomeration, is the use of sur-
factant in two stages: rst in the synthesis stage and second after
the particles formation. Under these conditions, due to presence of
surfactant molecules in the media from the beginning of the reac-
tion, the particle growth rate is diminished. Addition of surfactant
after the particles formation prevents the particles agglomeration
and tends to a more stable ferrouids. Through the synthesis of
nanoparticles [2830], herein, an ultrasonic-assisted approach has
been developed to prepare magnetite nanoparticles using cysteine
as the biocapping agent. Beside the use of ultrasonic irradiation,
inert gas ow through the reaction vessel, geometrical modication
of process container and addition of a proper surfactant resulted in
ferrouids with suitable size distributions and magnetic proper-
ties.
Superparamagnetic iron oxide nanoparticles (USPIO) can be
used as the MRI contrast agent for lymphatic system evaluation
[3134]. Iron oxide nanoparticles due to owning superparamag-
netic properties, can create magnetic eld around themselves while
being exposed to an external magnetic eld, hence T2 relaxiv-
ity increases as a result of rapid dephasing of the spins. Through
this so-called susceptibility effect, the signal decreases dramatically
[31,34].
Please cite this article in press as: R. Ahmadi, et al., Ultrasonic-assisted synthesis of magnetite based MRI contrast agent using cysteine as the
biocapping coating. Mater. Chem. Phys. (2011), doi:10.1016/j.matchemphys.2011.04.083
After intravenously injection of ferrouids, nanoparticles
accumulate in lymph nodes based on their size, which is fol-
lowed by maximum increase of T2 relaxivity approximately
1224 h after injection [33]. Biodistribution of USPIO particles
mainly depends on the particle size, surface coating and surface
charge.
2. Experimental procedure
2.1. Sample preparation
All the chemical reagents used in this research work were of analytical grade
and used as received without further purication. Fig. 1 shows the typical procedure
for the synthesizing magnetite nanoparticles. In the rst stage of this procedure,
pure argon was bubbled into the reactor containing 150 ml distilled water in order
to remove oxygen. Then, 6 mmol (1.20 g) FeCl2 4H2 O, 12 mmol (3.25 g) FeCl3 6H2 O
and 12 mmol (1.45 g) cysteine were added to the solution. The mixture was ultra-
sonicated for 10 min at room temperature and then was added into 4 M potassium
hydroxide (KOH) while ultrasound irradiation and blowing of pure argon were still
in progress. After ultrasonication of mixture at 60 C under argon atmosphere for
60 min, a dark suspension was obtained. The dark precipitate was extracted by cen-
trifuging the dark suspension. After washing the products with absolute ethanol and
drying at room temperature, they were dispersed in 12 mmol cysteine solution for
30 min by ultrasound at 25 C. In order to study the effect of size distribution on nal
MR images, three samples were synthesized with various size distributions ensuing
from three different elective pH values of solution; pH 12 (sample A), pH 11.5 (sam-
ple B) and pH 11 (sample C). The above-mentioned procedure was repeated three
times for each sample and the average results were reported in this work.
Dextran coated magnetite nanoparticles have been studied in many works
[35,36]. In order to compare MR properties of samples A, B and C with that of dex-
tran coated nanoparticles, sample D was prepared similar to sample A except that
dextran (40 KD) was used instead of cysteine. In this process, solution pH was equal
to 12 and the amount of dextran was 1.45 g.
2.2. Characterization instruments
X-ray diffraction (XRD) was performed by a Siemens D5000 X-ray diffractometer
using graphite-monochromatized high-intensity Cu K radiation ( = 1.5406 A). IR
spectra were recorded on a Nicolet spectrometer (Magna 500). Powder samples
were dried at 80 C before fabrication of KBr pellet. A JEOL TEM JEM-2010F was
used to determine the average particle size and morphology of the powders on an
accelerating voltage of 200 kV. Malvern instrument was employed for hydrodynamic
diameter measurement via DLS technique.
2.3. Cell culture and cytotoxicity assay
L929 cells were obtained from National Cell Bank of Iran (NCBI), Pasteur Insti-
tute of Iran. MTT assay was used to investigate the viability of L929 cells in media
containing RPMI1640 (80%, v/v), FBS (10%, v/v) and the ferrouid sample A (10%, v/v)
with various concentrations between 0.224 and 125 g (Fe)/ml. 0.16 ml of RPMI and
0.02 ml of FBS were distributed in wells of a 96-well plate. 0.02 ml of the ferrouid
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Fig. 2. XRD pattern of (a) sample A and (b) pure magnetite (JCPDS card no. 19-0629).
was inserted in each well too. The L929 cells containing solution of RPMI, FBS and
magnetite nanoparticles, were cultivated for 24 h in a 5% CO2 balanced-air incubator
at 37 C. The concentration of cells in each well was xed to 104 cells/ml by counting
initial cells with a haemacytometer. In each MTT test, the RPMI-FBS medium was
used as control without ferrouid. After 24 h of incubation, 0.04 ml of MTT solution
was added to each well, which was followed up by another 4 h of incubation. After
removing the medium, 0.05 ml of dimethyl sulfoxide (DMSO) was added to each well
to dissolve the formed crystals. Finally, light absorbance was measured at 540 nm
by ELISA plate reader. Each MTT test was conducted three times with 5 repetitions
for each ferrouid concentration and the average results were reported.
2.4. MRI studies
T1 and T2 relaxivities of the samples were evaluated by 1.5 T GE MR Scanner at
0.015, 0.008, 0.004, 0.002 and 0.000 (distilled water) mg(Fe)/ml concentrations at
25 C. All test vials were subsequently investigated for measurement of T1 relaxation
times by axial spine echo (SE) sequences with TR = 60 ms and TE = 11 ms. T2 relax-
ation times axial spine echo (SE) sequences were obtained with TR = 1000 ms and
TE = 10 ms. All pulse sequences were acquired with a 90 mm 90 mm eld of view
(FOV), a matrix of 256 196 pixels, a slice thickness of 5 mm and one acquisition.
For in vivo studies, all rats were approved by the animal care and use commit-
tee of Tehran Medical University. Rats were anaesthetized by pentobarbital sodium
at the dose of 40 mg kg1 body weight and xed in MRI system. Samples A, B and
C were administered in rats intravenously via lateral tail vein. MRI scan was per-
formed 24 h after administration of contrast agent at a dose of 2.5 mg (Fe)/kg body
weight. MRI studies were performed at 1.5 T using knee coil for transmission and
reception of the signal. T2*-GRE (TR = 460 ms; TE = 9 ms; FOV = 25 mm 25 mm; slice
thickness = 1.6 mm; ip angle = 15 ) was used for all studies.
3. Results and discussion
3.1. X-ray powder diffraction pattern
Fig. 2 shows a typical XRD pattern of the produced Fe3 O4
nanoparticles. Seven characteristic peaks were recognized in XRD
pattern of sample A. These peaks are well-matched with the mag-
netite characteristic peaks (JCPDS card no. 19-0629) conrming the
inverse spinel structure of synthesized particles.
3.2. FT-IR
The formation of Fe3 O4 nanoparticles and presence of cysteine
on nanoparticles was further characterized by FT-IR spectroscopy
as shown in Fig. 3. Infrared transmission spectrum of sample A
was recorded in the range of 4000400 cm1 . The transmittance
band at 592 cm1 is the stretching mode of FeO in Fe3 O4 [9]. FT-IR
Please cite this article in press as: R. Ahmadi, et al., Ultrasonic-assisted synthesis of magnetite based MRI contrast agent using cysteine as the
biocapping coating. Mater. Chem. Phys. (2011), doi:10.1016/j.matchemphys.2011.04.083
3
Fig. 3. A typical FT-IR spectrum of Fe3 O4 nanoparticles synthesized in the presence
of cysteine as capping agent. This result is belong to sample A.
spectra of sample A revealed the appearance of some bands among
16501100 cm1 which were assigned to the stretching of ethyl
and carbonyl groups and the characteristic absorptions of alkyl
stretching modes between 3000 and 3500 cm1 . These peaks were
recognized as the vibration of cysteine functional groups on the
surface of Fe3 O4 nanoparticles.
3.3. Transmission electron microscope (TEM) characterization
TEM images of Fe3 O4 nanoparticles with different pH values
are illustrated in Fig. 4. As it can be seen in this gure, the size
of nanoparticles is decreased by increasing pH value. Diffraction
pattern of sample C corresponds to inverse spinel structure of mag-
netite (Fig. 4c). The regular distribution of Fe3 O4 nanoparticles
is attributed to the ultrasonic irradiation and the use of cysteine
as the biocapping agent in this sample. With the onset of Fe3 O4
nuclei formation, carboxylic and mercaptan functional groups on
the cysteine, coordinate to the surface of the Fe3 O4 nanoparticles
leading to the formation of a six-membered chelate ring, as shown
in Fig. 5. Consequently, each nucleus would be surrounded by cys-
teine, which prohibits the excess growth of the nuclei, hence ne
nanoparticles are formed. Then, the second stage of adding sur-
factant in ultrasonicating conditions will reduce agglomeration.
Measuring 100 particles for each sample, the mean particle size
can be calculated as 10.02, 12.16 and 19.58 nm for samples A, B
and C, respectively. Mean particles size of sample D was equal to
11.13 nm (near to that of sample A).
3.4. Dynamic light scattering (DLS) diagrams
The size histogram of samples A, B and C are illustrated in
Fig. 6ac, respectively. These data were obtained from DLS mea-
surement. Hydrodynamic size of nanoparticles is decreased as the
pH value of the samples is increased. Mean hydrodynamic size of
29.2, 39.7 and 100.6 nm was obtained for samples A, B and C, respec-
tively. Reduction of pH from 12 to 11 results in the decrease of
particles surface charge. So, mean particle size and mean hydrody-
namic size increase through an aggregation mechanism. Besides,
the probability of aggregates formation with various hydrodynamic
sizes increase and thus, hydrodynamic size distribution is broader
in lower pHs. So, hydrodynamic size distribution of sample A is
sharper than those of samples B and C.
Mean hydrodynamic size of sample D was equal to 31.6 nm (near
to that of sample A).
3.5. Vibrating sample magnetometer (VSM) diagrams
Fig. 7ac shows VSM diagrams of samples A, B and C at room
temperature, respectively. Superparamagnetic behavior of samples
A and B is due to small particle size, while hysteresis behavior of
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Fig. 4. TEM micrographs of the Fe3 O4 nanoparticles: (a) sample A produced at pH 12, (b) sample B produced at pH 11.5 and (c) sample C produced at pH 11, scale bar is
10 nm.

Please cite this article in press as: R. Ahmadi, et al., Ultrasonic-assisted synthesis of magnetite based MRI contrast agent using cysteine as the
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Fig. 5. Proposed structure for interaction between cysteine and Fe3 O4 nanoparticle
surface.

Fig. 7. VSM diagrams of (a) sample A produced at pH 12, (b) sample B produced at
pH 11.5 and (c) sample C produced at pH 11.

sample C with Hc 10.5 Oe is related to the large particle size and

Fig. 6. Size histogram of: (a) sample A produced at pH 12, (b) sample B produced
at pH 11.5 and (c) sample C produced at pH 11. These data were obtained from DLS
measurements.
broad size distribution of Fe3 O4 nanoparticles. According to Fig. 7,
saturation magnetization of samples A, B and C were equal to 70.12,
71.35 and 71.77 emu g1 , respectively. These results are in good
coincidence with this fact that Ms increases with particle size. Sim-
ilar results can be seen for remanent magnetization of samples A,
B and C. Mr was near zero for samples A and B due to their small
particle size and superparmagnetic behavior, while it was equal to
4.83 emu g1 for sample C due to its large particle size (Fig. 7).
Saturation magnetization of sample D was equal to
69.55 emu g1 , while its Mr and Hc were near to zero due to
the superparamagnetic behavior.

Please cite this article in press as: R. Ahmadi, et al., Ultrasonic-assisted synthesis of magnetite based MRI contrast agent using cysteine as the
biocapping coating. Mater. Chem. Phys. (2011), doi:10.1016/j.matchemphys.2011.04.083
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Table 1
T1 relaxivity measurements for 4 concentration of dextran coated USPIO (sample
D) and samples A, B and C.

mg ml1 0.015 0.008 0.004 0.002 Water

Sample A Tl 257.3 483.1 1008.9 2130.4 2248.2

Sample B Tl 110.4 183.0 302.1 497.5 2248.2
Sample C Tl 125.4 234.5 420.9 891.3 2248.2
Sample D Tl 253.0 527.1 102.7 2193.0 2248.2

Table 2
T2 relaxivity measurements for 4 concentration of dextran coated USPIO (sample
D) and samples A, B and C.

mg ml1 0.015 0.008 0.004 0.002 Water

Fig. 8. Viability of L929 cells in various concentrations of magnetite nanoparticles Sample A T2 19.8 23.0 55.2 201.2 389.9
(n = 3). The cells were cultivated with ferrouid sample A. Sample B T2 18.9 22.9 39.3 67.8 389.9
Sample C T2 18.0 30.4 58.8 112.7 389.9
Sample D T2 22 1 24.7 50.8 150.7 389.9

3.6. Cell culture and cytotoxicity assay results
The results of cell culture in the medium containing ferrouid
sample A with various concentrations are presented in Fig. 8
(ANOVA, p < 0.05). Since cell viability in all concentrations is more
than 90%, the ferrouid biocompability seems to be in appropriate
range.
3.7. MR imaging
As shown in Fig. 9, the obtained nanoparticles are able to
affect T1 and T2 contrast in a concentration dependent manner.
A dose dependent signal intensity decrease is seen on T1 weighted
images and dose dependent signal intensity increase is noted on
T2 weighted images. In comparison, samples A and C had higher
T1 and T2 relaxation times and therefore higher signal in the same
concentrations than sample B. Comparison between the dextran
coated USPIO and sample A demonstrated approximately similar
T1 and T2 relaxation times (Tables 1 and 2). The results show that
particle size has a signicant effect on T1 and T2 relaxation times.
As it can be observed in MR images, dramatic decrease of sig-
nal intensity in rat lymph nodes, conrms the susceptibility effect
and the existence of magnetite nanoparticles (Fig. 10). According
to these images, 24 h after IV injection of sample A, inguinal, lum-
bar, cervical and auxiliary lymph nodes were visualized. As it is
explained by theory [37], large and aggregated particles are mainly
accumulated in tissues such as liver and spleen, however smaller
ones (2040 nm) are phagocytosed by macrophages of lymphatic
system which enhance the image contrast of target tissues through
substantial shortening of T2 relaxation time. After animal injec-
tion, sample B creates susceptibility changes in some suspicious
lymph nodes, which is not true about sample C due to its relatively
larger size and lower plasma half-life (Fig. 11a and b, respectively).
In general, sample A shows the best biodistribution due to suitable
particle size and coating, and low coercivity. In all particle solutions,
no sign of decomposition and loss of solubility were observed even
after several months of storage at room temperature.

Fig. 9. Representative T1-weighted (TR = 60, TE = 10) and T2-weighted (TR = 1000, TE = 10) images of sample vials. images were obtained at 1.5 T. From top to bottum 0.015,
0.008, 0.004, 0.002 mg ml1 and water.

Please cite this article in press as: R. Ahmadi, et al., Ultrasonic-assisted synthesis of magnetite based MRI contrast agent using cysteine as the
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Fig. 10. Coronal T2* Images 24 h after IV injection of sample A at a dose of 2.5 mg (Fe)/kg body weight; auxiliary, cervical and lumbar lymph nodes are visualized. MRI studies
were performed at 1.5 T using knee coil for transmission and reception of the signal. T2*-GRE (TR 460 ms; TE 9ms; FOV 25 mm 25 mm; slice thickness 1.6 mm; ip angle 15
were used for all studies).

Fig. 11. (a) Coronal T2* Images 24 h after injection of sample B at a dose of 2.5 mg (Fe)/kg body weight. Some suspicious lumbar lymph nodes were seen. (b) Coronal T2*
Images 24 after injection of sample C at a dose of 2.5 mg (Fe)/kg body weight. There was no evidence of lymph node enhancement.

4. Conclusion potential MRI contrast enhancement agent. This approach leads to

formation of nanometric magnetite particles with mean particle
In summary, an ultrasonic-assisted approach is presented for size of 1020 nm and large saturation magnetizations of more than
preparation of cysteine-capped Fe3 O4 nanoparticles as a new 70 emu g1 . Biocompatibility of synthesized ferrouids was evalu-

Please cite this article in press as: R. Ahmadi, et al., Ultrasonic-assisted synthesis of magnetite based MRI contrast agent using cysteine as the
biocapping coating. Mater. Chem. Phys. (2011), doi:10.1016/j.matchemphys.2011.04.083
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ated via MTT assay with L929 cells which demonstrated acceptable
viability of incubated cells (more than 90%). In vitro and ani-
mal studies showed that the synthesized ferrouids with mean
hydrodynamic size of 29.2 and 39.7 nm are well applicable for MR
imaging lymphatic system as contrast agent, while larger agglom-
erates (mean hydrodynamic size = 100.6 nm) are not accumulated
in lymph nodes.
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