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Highly water-dispersible PEG surface modified ultra small superparamagnetic

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Nanotechnology 19 (2008) 365603 (7pp) doi:10.1088/0957-4484/19/36/365603

Highly water-dispersible PEG surface

modified ultra small superparamagnetic
iron oxide nanoparticles useful for
target-specific biomedical applications
Ja Young Park1 , Patel Daksha1 , Gang Ho Lee1,3 , Seungtae Woo2
and Yongmin Chang2
1
Department of Chemistry, College of Natural Sciences, Kyungpook National University,
Taegu 702-701, Korea
2
Department of Diagnostic Radiology, School of Medicine, Kyungpook National University
and Hospital, Taegu 702-701, Korea

E-mail: ghlee@mail.knu.ac.kr

Received 16 May 2008, in final form 25 June 2008

Published 28 July 2008
Online at stacks.iop.org/Nano/19/365603

Abstract
For the application of superparamagnetic iron oxide nanoparticles in biomedical fields for
target-specific purposes, they should be ultra small in diameter. We developed a simple one-step
synthesis of surface modified ultra small superparamagnetic iron oxide nanoparticles
(USPIONs) with an average particle diameter of 1.7 nm in a polar organic solvent. Polyethylene
glycol diacid (PEG) surface modified USPIONs synthesized in triethylene glycol were nearly
monodisperse in diameter and highly water-dispersible. The PEG surface modified USPIONs
were tested for use as magnetic resonance (MR) contrast agents. They had a low r2 /r1
relaxivity ratio of 3.4 (r1 = 4.46 and r2 = 15.01 mM−1 s−1 ) and showed clear dose-dependent
T1 and T2 map images, indicating that they will be useful as both target-specific T1 and T2 MR
contrast agents due to their ultra small size.
(Some figures in this article are in colour only in the electronic version)

1. Introduction
Superparamagnetic iron and iron oxide nanoparticles have
drawn special attention from both chemists and radiologists
because they can be used as magnetic resonance (MR) contrast
agents [1–13]. This is because superparamagnetic iron and iron
oxide nanoparticles possess high saturation magnetizations
and are also less toxic than other metal and metal oxide
nanoparticles. We report on a simple one-step synthesis of
highly water-dispersible, polyethylene glycol diacid (PEG)
surface modified ultra small superparamagnetic iron oxide
nanoparticles (USPIONs) with an average particle diameter of
1.7 nm. We tested them for use as MR contrast agents.
Among superparamagnetic iron oxide nanoparticles, US-
PIONs can be used for target-specific biomedical applications
3 Author to whom any correspondence should be addressed.
because they can transmigrate the capillary wall [11]. The
target-specific capability will minimize a dose of a contrast
agent but will maximize a probe signal. It will also allow
us to obtain a high resolution MR image. Until now USPI-
ONs have been exclusively synthesized in non-polar organic
solvents [14–19]. However, they are only dispersible in non-
polar organic solvents, and thus should be surface modified by
hydrophilic and bio-compatible ligands before biomedical ap-
plications.
In general, nanoparticles suitable for biomedical applica-
tions should be (1) highly water-dispersible, (2) monodisperse
in diameter, and (3) surface modified by bio-compatible and
hydrophilic polymers. The PEG surface modified USPIONs
synthesized in this work seem to satisfy all of these specifi-
cations. In addition to these, the average nanoparticle diame-
ter of the USPIONs is estimated to be 1.7 nm, which is likely
the smallest iron oxide nanoparticle reported so far. This ultra

0957-4484/08/365603+07$30.00 1 © 2008 IOP Publishing Ltd Printed in the UK

Nanotechnology 19 (2008) 365603
Figure 1. A scheme for the one-step synthesis of the PEG surface
modified USPIONs. Three chemicals (FeCl3 ·6H2 O, polyethylene
glycol diacid (PEG), and triethylene glycol) were mixed together
and then refluxed at 260 ◦ C for 24 h under magnetic stirring and
an air flow.
small iron oxide nanoparticle may function as a real molecular
MR probe.
We used a polar organic solvent in this work. We find
that the synthesis in a polar organic solvent possesses both
merits that the syntheses in non-polar organic and aqueous
solvents have. The former provides a monodisperse particle
diameter, whereas the latter provides an easy synthesis for
biocompatibility. The synthesis in a polar organic solvent can
be carried out like the aqueous phase synthesis by using iron
salt as an iron precursor because the iron salt is soluble in
a polar organic solvent. Furthermore, nanoparticles can be
also simultaneously surface modified by a hydrophilic and bio-
compatible polymer because the polymer is also soluble in a
polar organic solvent. The nanoparticles thus produced are
nearly monodisperse in diameter as in the non-polar organic
phase synthesis and an immediate water solubility of the
surface modified nanoparticles makes their further biomedical
applications easy.
2. Experimental details
2.1. Chemicals
The chemicals used are ferric chloride hexahydrate (FeCl3 ·
6H2 O, 99%), triethylene glycol (99%), and polyethylene
glycol diacid (PEG) ( Mn = ∼600) which were all purchased
from Aldrich, and air which was purchased from a local
distributor. These chemicals and air were used without further
purification.
2.2. Synthesis
Bio-compatible PEG surface modified USPIONs were synthe-
sized as follows (figure 1). Only three chemicals were em-
ployed in the synthesis. These include triethylene glycol as a
polar organic solvent, FeCl3 ·6H2 O as an iron precursor, and
polyethylene glycol diacid (PEG) as a surface coating hy-
drophilic bio-compatible polymer. 1351 mg of FeCl3 ·6H2 O
(5 mmol) and 2.6 ml of PEG (5 mmol) were added into 20 ml
of triethylene glycol. The mixture was refluxed at 260 ◦ C for
24 h while it was magnetically stirred under an air flow. The
mixture cooled to room temperature. To separate the PEG sur-
face modified USPIONs from the reaction mixture, and thus
to obtain a powder sample, acetone was added to the reaction
2
J Y Park et al
mixture. The top solution was decanted and the remaining so-
lution was dried in air. The powder sample was, however, read-
ily redispersed in distilled water. This synthesis is of low cost,
and can be carried out on a large scale just by expanding the
reaction scale.
2.3. Characterization
The particle size of USPIONs was measured with a high
resolution transmission electron microscope (HRTEM) with a
field emission filament at an acceleration voltage of 200 kV
(JEOL, JEM 2100F). For TEM measurement, a small amount
of either the solution or powder sample was diluted with
methanol (Aldrich, >99.9%), and then a drop of the dispersion
was deposited on a copper grid covered with an amorphous
carbon membrane. The copper grid was left in air for an
hour for the sample to be dried. The crystal structure of the
USPIONs was determined with an x-ray diffraction (XRD)
spectrometer with unfiltered Cu Kα radiation of 1.541 84 Å
(Philips, X-PERT). The XRD patterns of powder samples were
recorded between 2θ = 20◦ –90◦ . Surface coating of the
USPIONs by PEG was characterized with a Fourier transform
infrared (FTIR) absorption spectrometer (Mattson Instruments,
Inc., Galaxy 7020A). To record an FTIR absorption spectrum,
a pallet was prepared by pressing a mixture of powder
sample and KBr powder. We performed a thermo-gravimetric
experiment by using a thermo-gravimetric analyzer (TGA;
TA Instruments, SDT Q 600) to estimate the net mass of
the USPIONs in the PEG surface modified USPIONs. The
temperature was varied between room temperature and 700 ◦ C,
and air flowed during the TGA experiment. This net mass
of the USPIONs thus obtained was used to correct the
magnetizations. The magnetic properties of the USPIONs
were measured with a superconducting quantum interference
device (SQUID) magnetometer (Quantum Design, MPMS-7).
Both hysteresis loops ( M – H curves) (−5  H  5 T) at
temperatures T = 5 and 300 K and zero field cooled (ZFC)
and field cooled (FC) magnetization curves versus temperature
( M –T curves) (3  T  330 K) at an applied field H =
100 Oe were recorded. The hydrodynamic diameter of the
PEG surface modified USPIONs was measured with a dynamic
light scattering (DLS) particle size analyzer (Microtrac, UAP-
150). To measure the hydrodynamic diameter, the sample
solution was diluted with distilled water. An inductively
coupled plasma atomic emission spectrometer (ICPAES;
Thermo Jarrell Ash Co., IRIS/AP) was used to measure the
iron concentration (x ) in parts per million (ppm) in the sample
solution. Note that x ppm corresponds to (x/55.85) mM Fe.
Using a sample solution of 1623 ppm (1623 mg Fe l−1 or
29.1 mM Fe), five different iron concentrations (i.e., 0.0625,
0.125, 0.25, 0.5, and 1.0 mM Fe) of the PEG surface modified
USPIONs in distilled water were then prepared by diluting
an appropriate volume of the above sample solution with
distilled water. These solutions were used to measure both
the relaxation times and map images of the PEG surface
modified USPIONs. The relaxation times and map images
were measured with a magnetic resonance imaging (MRI)
instrument (GE 1.5 T, Excite) equipped with a Knee coil
Nanotechnology 19 (2008) 365603
Figure 2. A series of TEM micrographs of the PEG surface modified USPIONs taken at (a) 50, (b) and (c) 5 nm scales. The dotted square in
(b) is magnified in (c). (d) A DLS pattern of the PEG surface modified USPIONs showing a hydrodynamic diameter of 5.4 nm.
(EXTREM) to test the PEG surface modified USPIONs for
use as an MR contrast agent. The parameters used for
measurements of T1 and T2 relaxation times are external field
H = 1.5 T, temperature = 22 ◦ C, NEX = 1, FOV = 20 cm,
phase FOV = 1, frequency × phase = 320 × 160, slice
thickness = 5 cm, spacing (gap) = 1 cm, and bandwidth =
15.63. For measurements of the T1 relaxation time, the
repetition time (TR) and echo time (TE) were set at values of
2000 and 29 ms, respectively, and the MR signal was measured
by changing the inversion time (TI), such as 1750, 50, 1700,
100, 1650, 150, 1600, 200, 1550, 250, 1500, 300, 1450, 350,
1400, 400, 1350, 450, 1300, 500, 1250, 550, 1200, 600, 1150,
650, 1100, 700, 1050, 750, 1000, 800, 950, 850, 900. From
the curve fitting, the T1 relaxation time was obtained. For
measurements of the T2 relaxation time, TR was set at value
of 2000 ms and the MR signal was measured by changing a
set of TE1 and TE2 values such as (10, 30), (60, 90), (120,
150), (180, 210), (240, 270), (300, 350), (400, 450), (500, 550),
(600, 650), (700, 750), (800, 850), (900, 950), (1000, 1100),
(1200, 1300), (1400, 1500), (1600, 1700), (1800, 1900). From
the curve fitting, the T2 relaxation time was obtained. This
procedure was repeated for five iron concentrations to obtain
both T1 and T2 relaxation times. Finally, relaxivities r1 and r2
3
J Y Park et al
of the PEG surface modified USPIONs were obtained from the
linear curve fittings of the T1 and T2 relaxation times versus
concentration, respectively.
3. Results and discussion
3.1. Particle size, crystal structure, and magnetic properties
Figures 2(a)–(c) show a series of low and high resolution
TEM micrographs of PEG surface modified USPIONs. Since
the PEG coating does not affect TEM measurement, the
nanoparticles shown in figures 2(a)–(c) correspond to the
USPIONs. The USPIONs are nearly monodisperse in
diameter. From these TEM micrographs, the average particle
diameter of the USPIONs was estimated to be 1.7 ± 0.3 nm.
The magnified lattice image in figure 2(c) clearly shows that
the lattice spacing ( L 311 ) of the (311) lattice plane is 0.254 ±
0.03 nm. This value is consistent with the reported value of
bulk spinel iron oxide such as magnetite (Fe3 O4 ) or maghemite
(γ -Fe2 O3 ) [20, 21]. The hydrodynamic diameter of the PEG
surface modified USPIONs measured by using a DLS particle
size analyzer is 5.4 nm (figure 2(d)). This diameter is larger
than the value measured by the TEM micrograph due to both
Nanotechnology 19 (2008) 365603
0 weight per cent of the USPIONs in the PEG surface modified
Figure 3. (a) XRD patterns of the PEG surface modified USPIONs,
the well-crystallized magnetite (Fe3 O4 ) nanoparticles, and the PEG.
Vertical dotted lines are drawn to indicate the peak positions of the
magnetite. (b) A TGA curve of the PEG surface modified USPIONs,
showing that the weight per cent of the USPIONs in the PEG surface
modified USPIONs is 30.65%.
surface coating of the USPIONs by the PEG and the water
solvation around the PEG surface modified USPIONs.
X-ray diffraction (XRD) patterns of PEG surface modified
USPIONs, the well-crystallized magnetite nanoparticles, and
the PEG are provided in figure 3(a). The latter two are
provided as references in order to distinguish the peaks of
the USPIONs from those of the PEG. As expected, the broad
(due to the ultra small size of the USPIONs [22]) and low
intensity peaks of the USPIONs significantly overlapped with
the sharp peaks of the PEG. A close examination shows that the
(311) and the (440) peaks of the USPIONs corresponding to a
Figure 4. (a) ZFC and FC M –T curves at an applied field H = 100 Oe (3  T  330 K), showing a TB of 9 K and (b) M – H curves at
temperatures T = 5 and 300 K (−5  H  5 T).
4
J Y Park et al
face-centered cubic structure of the spinel iron oxide such as
magnetite or maghemite can be assigned. Note that, in very
small iron oxide nanoparticles such as USPIONs, it is very
difficult to distinguish between these two spinel structures with
XRD patterns and HRTEM micrographs. The peaks of the
PEG which appeared in the XRD pattern of the PEG surface
modified USPIONs are likely related to the PEG which is
grafted at the USPIONs probably because of the high mass of
the PEG ( Mn = ∼600 amu). As will be discussed later, we did
not observe the C=O stretching excitation in the PEG surface
modified USPIONs in the FTIR spectrum, implying that free
COOHs do not exist in the PEG surface modified USPIONs.
If PEG not grafted at the USPIONs were to exist, they should
have possessed free COOHs, and thus contributed to the C=O
stretching excitation.
To estimate how much the USPIONs are coated by PEG,
we estimated a weight per cent of the USPIONs in the
PEG surface modified USPIONs by performing a thermo-
gravimetry experiment by using a TGA. Figure 3(b) shows a
TGA curve. At ∼210 ◦ C, there is a drop in mass due to the
combustion of the PEG via reaction with oxygen, and then
the curve becomes nearly flat, which is due to the remaining
mass of the USPIONs. From the TGA curve, we estimated the
USPIONs to be 30.65%. This weight per cent was used to
estimate the net magnetization of the USPIONs in the PEG
surface modified USPIONs.
By using the weight per cent of USPIONs in PEG surface
modified USPIONs as estimated above, we corrected the
magnetizations. Zero field cooled (ZFC) and field cooled (FC)
magnetization curves versus temperature (3  T  330 K)
at an applied field H = 100 Oe are provided in figure 4(a),
clearly showing a superparamagnetic behavior of the USPIONs
with a blocking temperature (TB ) of 9 ± 1 K. Hysteresis loops
( M – H curves) (−5  H  5 T) at temperatures T = 5
and 300 K were also recorded (figure 4(b)). The M – H curve
at 5 K shows a hysteresis with coercivity of 270 ± 5 Oe
and remanence of 1.0 ± 0.1 emu g−1 , indicating that the
USPIONs are ferromagnetic at 5 K, whereas that at 300 K
shows no hysteresis and zero coercivity, indicating that the
USPIONs are superparamagnetic at 300 K. However, the M –
H curves are not saturated even at H = ±5 T. Note that
an unsaturated M – H curve similar to ours was also observed
for the spinel iron oxide nanoparticles with a mean diameter
Nanotechnology 19 (2008) 365603
of 2.06 nm at room temperature by Yaacob et al [23]. They
attributed this to a magnetically anomalous surface layer. The
magnetizations at H = 5 T estimated from the M – H curves
at T = 5 and 300 K are 23.5 and 6.6 emu g−1 , respectively.
These magnetizations are smaller than the bulk saturation
magnetization of 84 emu g−1 for magnetite or 74 emu g−1
for maghemite [24], as also observed in ferrite and iron
nanoparticles [25–27]. This smaller magnetization as well as
the unsaturation at H = ±5 T is likely related to the ultra small
size of the USPIONs with deteriorated surface spins. Surface
spins can be easily contaminated by surface coating materials
such as the PEG in this work. This surface spin effect will
be especially large for ultra small nanoparticles such as the
USPIONs because of the large surface to volume ratio.
As mentioned by Carpenter [28], the slope near zero
field in an M – H curve for superparamagnetic nanoparticles
with a size distribution comes from the largest nanoparticles.
By using the equation given in [28], i.e., dmax =
[ 18kT (dπρM/Md2H ) H =0 ]1/3 , in which dmax is the maximum magnetic
S indicated by the three vertical lines) overlapping each other.
diameter, k the Boltzmann constant, T the temperature
(300 K), ρ the density of USPIONs, and (d M/d H ) H =0 the
slope near zero field (0.28 × 10−3 emu g−1 Oe), and assuming
that the saturation magnetization corresponds to the bulk spinel
iron oxide, the dmax is estimated to be ∼1.26 nm by using an
average saturation magnetization of 79 emu g−1 for magnetite
and maghemite and the ρ of magnetite (5.19 g cm−3 ). This
value is somewhat smaller than the one (1.7 nm) observed in
the TEM micrograph. If the surface spins are deteriorated by
the PEG, the magnetic diameter thus obtained will be smaller
than the physical diameter observed in a TEM micrograph
because the former will then correspond to a core diameter.
3.2. Surface coating
Figure 5 shows FTIR spectra of PEG and PEG surface modified
USPIONs. The peak at 585 cm−1 arises from the Fe–O stretch
vibration (i.e., the ν1 band) of the USPIONs [29–31]. The
water stretch at 3410 cm−1 , the C–H stretch at 2890 cm−1 ,
and the C–O stretch at 1110 cm−1 were observed in both
the PEG and the PEG surface modified USPIONs. The
latter two confirm that the USPIONs are surface modified
by the PEG. The C=O stretch at 1745 cm−1 in the PEG
is, however, not prominent in the PEG surface modified
USPIONs. Instead, several peaks overlapped with one another
around 1645 cm−1 are observed (see the enlarged figure inset
in figure 5). This shift is primarily due to the COO− –
Fe bond formation as shown in figure 1. The water bend
vibration also occurs in this region (∼1600 cm−1 ), and
thus will contribute to the overlapping. Several kinds of
dicarboxylic acid adsorbed on TiO2 have been thoroughly
studied via ATR-FTIR spectroscopy [32, 33]. In those works,
by increasing the carbon chain length (n ) from oxalic (n = 0)
to succinic acids (n = 2), the typical C=O absorption around
1710 cm−1 disappeared [33]. Instead, strong absorptions
below 1700 cm−1 were observed like in the present work. This
was because all of four oxygen atoms in the dicarboxylic acid
were bound to metal atoms [33], like the bonding structure
shown in figure 1. This explains our observation.
5
J Y Park et al
Figure 5. FTIR spectra of the PEG surface modified USPIONs and
the PEG. The inset is an expanded figure around the 1645 cm−1
region of the PEG surface modified USPIONs to show that the peak
at the 1645 cm−1 region consists of several peaks (at least three as
3.3. Relaxivities and map images
In order to test PEG surface modified USPIONs for use as MR
contrast agents, relaxivities and map images were investigated.
First, to measure the relaxivities, the longitudinal T1 and the
transverse T2 relaxation times were first measured at five iron
concentrations (0.0625, 0.125, 0.25, 0.5, and 1.0 mM) at
field strength (H ) = 1.5 T and 22 ◦ C. Inverse relaxation
times (1/T1 and 1/T2 ) were then plotted as a function of
iron concentration, respectively (figures 6(a) and (b)). The
longitudinal r1 and the transverse r2 relaxivities were then
estimated from the slopes of the plots to be 4.46 ± 0.04 and
15.01 ± 0.54 mM−1 s−1 , respectively. The r2 /r1 ratio is as low
as 3.4, implying that for clinical field strengths (0.5–3.0 T),
spin relaxation of the USPIONs is dominated by both T1 and
T2 relaxation processes. This suggests that the PEG surface
modified USPIONs will function as both T1 and T2 MR probes.
As a comparison, monocrystalline iron oxide nanocompounds
(MIONs) with the particle diameter of 4.6 nm had a ratio of 2.1
at 0.47 T and 37 ◦ C (r1 = 16.5 and r2 = 34.8 mM−1 s−1 ) [12].
Note that this ratio generally increases as the field strength
increases. This implies that our ratio will be even smaller
than 3.4 at lower field strengths. For superparamagnetic
iron oxides (SPIOs) with the particle diameter of 12 nm, the
r2 /r1 ratio was reported to be 205.8 at 7 T (r1 = 1.2 and
r2 = 247 mM−1 s−1 ) [13]. This high ratio indicates that the
SPIOs can be only used as a T2 MR contrast agent because
spin relaxation of the SPIOs is heavily dominated by the T2
relaxation process.
T1 and T2 map images were produced by converting T1
and T2 relaxation times measured above into color maps such
that the color map becomes dark red as the sample has a
shorter relaxation time. As presented in figures 7(a) and (b),
respectively, both T1 and T2 map images clearly show dose-
dependent contrast changes from thin yellow to dark red as
the iron concentration increases. This is because both T1
and T2 relaxation times become shorter with increasing iron
Nanotechnology 19 (2008) 365603
Figure 6. Plots of inverse relaxation times (a) 1/T1 and (b) 1/T2 as a
function of iron concentration (0.0625, 0.125, 0.25, 0.5, and 1.0 mM
Fe). The slopes correspond to (a) the longitudinal r1 and (b) the
transverse r2 relaxivities, respectively.
concentration. In terms of a signal intensity ( I ), the I1
for the T1 relaxation process increases with increasing iron
concentration because I1 ∝ (1 − e−TR/T 1 ) in which TR
is the repetition time. However, I2 for the T2 relaxation
process decreases with increasing iron concentration because
I2 ∝ e−TE/T 2 in which TE is the echo time. This means
that in a typical MR image, the T1 MR contrast image will
become whiter with increasing iron concentration, whereas the
T2 MR contrast image will become darker with increasing iron
concentration.
PEG surface modified USPIONs should be well dispersed
in aqueous solution for biomedical applications. A sample
solution is presented in figure 7(c), showing a good dispersion
or a high colloidal stability of the PEG surface modified
USPIONs in aqueous solution. To quantitatively discuss
solubility, 1623 ppm (1623 mg Fe l−1 or 29.1 mM Fe) of
the PEG surface modified USPIONs estimated by using an
ICPAES, showed that they were stable as colloids for at
least more than one month, as shown in figure 7(c). A
powder sample is also provided in figure 7(d). Note that the
powder sample can be readily redispersed in distilled water, as
mentioned before.
3.4. Possibility for use as a target-specific MR contrast agent
The great potential of PEG surface modified USPIONs lies in
their ultra small size. This ultra small size can also lead to
6
J Y Park et al
Figure 7. (a) Longitudinal T1 and (b) transverse T2 map images of
the PEG surface modified USPIONs in distilled water. From left to
right, the iron concentrations are 0.0625, 0.125, 0.25, 0.5, and
1.0 mM Fe. Photographs of (c) a well-dispersed aqueous solution of
the PEG surface modified USPIONs and (d) a powder sample.
good transport properties, such as a high mobility in water4 ,
which are very important for biomedical applications because
after being injected, the PEG surface modified USPIONs must
diffuse as quickly as possible. As a comparison, the mass of an
USPION itself is roughly estimated to be ∼12 000 daltons5 ,
which is somewhat close to the mass of a myoglobin [34]
(17 000 daltons, d = ∼3.3 nm, and D = 1.06 × 10−10 m2 s−1
in which D is the diffusion coefficient in water at 20 ◦ C).
The total mass of a PEG surface modified USPION including
the surface coating PEG is estimated to be ∼39 000 daltons
by using a weight per cent (69.35%) of the PEG estimated
from the TGA analysis. This is smaller than the mass of a
hemoglobin [34] (68 000 daltons, d = ∼8.5 nm, and D =
7.04 × 10−11 m2 s−1 ). Just based on the mass, we expect that
the transport properties of the PEG surface modified USPIONs
will be those between a myoglobin and a hemoglobin.
As mentioned before, the PEG surface modified USPIONs
can transmigrate the capillary wall due to their ultra small
size [11], and thus can be used for target-specific biomedical
applications. Note that conventional large superparamagnetic
iron oxide nanoparticles (d > 20 nm) which are mainly used
as T2 MR contrast agents for the liver, cannot transmigrate
the capillary wall due to their large size. With the transport
properties which are expected to be similar to those between
a myoglobin and a hemoglobin as mentioned above and the
target-specific capability due to the ultra small size, the PEG
surface modified USPIONs can be applied to a variety of
target-specific biomedical areas. These may include (1) non-
specific MR contrast agents for various organs including brain
and lymphatic system, (2) target-specific MR contrast agents of
tumors when combined with suitable antibodies, and (3) target-
specific drug deliveries when combined with both antibodies
and drugs.
4 The mobility is proportional to the diffusion coefficient ( D ) via the Einstein
relation. For biological molecules, D ranges from 10−10 to 10−11 m2 s−1 in
water at 25 ◦ C.
5 The mass (m ) of a PEG surface modified USPION is roughly estimated
by adding the mass (m 1 ) of the PEGs to the mass (m 2 ) of an USPION.
The m 2 is roughly N w in which N and w are the average number and the
average mass of three ions (Fe2+ , Fe3+ , O2− ) in an USPION, respectively.
N ≈ 0.74(R/r)3 = 370 ( R , the average radius of an USPION = 0.85 nm
and r , the average radius of three ions = ∼0.107 nm). Thus, m 2 =
∼370 × (55.85 × 3 + 16 × 4)/7 = 12 000 daltons. From the TGA analysis, the
weight per cent of PEG was 69.35%. Thus, m 1 = ∼27 000 daltons. Finally,
we obtained m = m 1 + m 2 = ∼39 000 daltons.
Nanotechnology 19 (2008) 365603
4. Conclusions
To summarize, we prepared highly water-dispersible PEG
surface modified ultra small superparamagnetic iron oxide
nanoparticles (USPIONs) (core d = 1.7 nm) by a simple one-
step synthesis. We investigated the r1 and r2 relaxivities and
T1 and T2 map images of the PEG surface modified USPIONs
to test them for use as MR contrast agents. We observed that
the PEG surface modified USPIONs possessed high r1 and r2
relaxivities (r1 = 4.46 and r2 = 15.01 mM−1 s−1 ) with a low
r2 /r1 ratio of 3.4 at 1.5 T and 22 ◦ C, and showed clear dose-
dependent T1 and T2 map images, proving that the PEG surface
modified USPIONs can be used as both T1 and T2 MR contrast
agents. These dual MR capabilities originate from the ultra
small size of the USPIONs.
Acknowledgments
This project was supported by a Grant (No. RTI04-01-01)
from the Regional Technology Innovation Program of the
Ministry of Commerce, Industry, and Energy (MOCIE) by the
Korean Government. We are grateful for the partial support of
the Korea Research Foundation Grant funded by the Korean
Government (MOEHRD) (KRF-2006-521-C00081) and the
Advanced Basic Research Laboratory of the Korea Research
Foundation (R14-2003-033-01000-1). We thank the Korea
Basic Science Institute for allowing us to use their HRTEM,
DLS particle size analyzer, SQUID magnetometer, and XRD
spectrometer.
References
[1] Pankhurst Q A, Connolly J, Jones S K and Dobson J 2003
J. Phys. D: Appl. Phys. 36 R167–81
[2] Tartaj P, Morales M P, Veintemillas-Verdaguer S,
González-Carreño T and Serna C J 2003 J. Phys. D: Appl.
Phys. 36 R182–97
[3] Berry C C and Curtis A S G 2003 J. Phys. D: Appl. Phys.
36 R198–206
[4] Salata O V 2004 J. Nanobiotechnol. 2 3
[5] Cho S-J, Jarrett B R, Louie A Y and Kauzlarich S M 2006
Nanotechnology 17 640–4
[6] Billotey C, Wilhelm C, Devaud M, Bacri J C, Bittoun J and
Gazeau F 2003 Magn. Reson. Med. 49 646–54
[7] Wunderbaldinger P, Josephson L and Weissleder R 2002
Acad. Radiol. 9 S304–6
[8] Tiefenauer L X, Tschirky A, Kühne G and Andres R Y 1996
Magn. Reson. Imaging 14 391–402
View publication stats
J Y Park et al
[9] Jung C W and Jacobs P 1995 Magn. Reson. Imaging
13 661–74
[10] Widder D J, Greif W L, Widder K J, Edelman R R and
Brady T J 1987 Am. J. Radiol. 148 399–404
[11] Weissleder R, Elizondo G, Wittenberg J, Rabito C A,
Bengele H H and Josephson L 1990 Radiology 175 489–93
[12] Shen T, Weissleder R, Papisov M, Bogdanov A and Brady T J
2005 Magn. Reson. Med. 29 599–604
[13] Chapon C, Franconi F, Lemaire L, Marescaux L, Legras P,
Saint-André J P, Denizot B and Jeune J-J 2003 Invest.
Radiol. 38 141–6
[14] Sun S, Zeng H, Robinson D B, Raoux S, Rice P M, Wang S X
and Li G 2004 J. Am. Chem. Soc. 126 273–9
[15] Sun S and Zeng H 2002 J. Am. Chem. Soc. 124 8204–5
[16] Rockenberger J, Scher E C and Alivisatos A P 1999 J. Am.
Chem. Soc. 121 11595–6
[17] Park J, An K, Hwang Y, Park J G, Noh H J, Kim J Y, Park J H,
Hwang N M and Hyeon T 2004 Nat. Mater. 3 891–5
[18] Hyeon T, Lee S S, Park J, Chung Y and Na H B 2001
J. Am. Chem. Soc. 123 12798–801
[19] Jana N R, Chen Y and Peng X 2004 Chem. Mater. 16 3931–5
[20] Card Number 19-0629 1997 JCPDS International Center for
Diffraction Data V. 1.30.
[21] Card Number 39-1346 1997 JCPDS International Center for
Diffraction Data V. 1.30.
[22] Cullity B D 1978 Elements of X-Ray Diffraction (Reading, MA:
Addison-Wesley) p 99
[23] Yaacob I I, Nunes A C and Bose A 1995 J. Colloid Interface
Sci. 171 73–84
[24] O’ Handley R C 2000 Modern Magnetic Materials, Principles
and Applications (New York: Wiley) p 125
[25] Gangopadhyay S, Hadjipanayis G C, Dale B, Sorensen C M,
Klabunde K J, Papaefthymiou V and Kostikas A 1992
Phys. Rev. B 45 9778–86
[26] Li Q, Sorensen C M, Klabunde K J and Hadjipanayis G C 1993
Aerosol Sci. Technol. 19 453–67
[27] Zhang D, Klabunde K J and Sorensen C M 1998 Phys. Rev. B
58 14167–70
[28] Carpenter E E 2001 J. Magn. Magn. Mater. 225 17–20
[29] Yamaura M, Camilo R L, Sampaio L C, Macêdo M A,
Nakamura M and Toma H E 2004 J. Magn. Magn. Mater.
279 210–7
[30] Ma M, Zhang Y, Yu W, Shen H, Zhang H and Gu N 2003
Colloids Surf. A 212 219–26
[31] Bruce I J, Taylor J, Todd M, Davies M J, Borioni E,
Sangregorio C and Sen T 2004 J. Magn. Magn. Mater.
284 145–60
[32] Mendive C B, Bredow T, Blesa M A and Bahnemann D W
2006 Phys. Chem. Chem. Phys. 8 3232–47
[33] Hug S J and Bahnemann D 2006 J. Electron Spectrosc. Relat.
Phenom. 150 208–19
[34] Riveros-Moreno V and Wittenberg J B 1972 J. Biol. Chem.
247 895–901