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SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES

FOR BIO-MEDICAL APPLICATIONS


D.K. Kim
1
, Y. Zhang
1
, W. Voit
2
, K.V. Rao
2
, J. Kehr
3
, B. Bjelke
4
and
M. Muhammed
1
1
Materials Chemistry Division and
2
Engineering Materials Physics Division, Royal Institute of
Technology, SE-100 44 Stockholm, Sweden
3
Division of Cellular and Molecular Neurochemistry,
Karolinska Institutet, SE-171 77 Stockholm, Sweden
4
MRI-Center, Experimental Unit, Karolinska
Institutet, SE-171 76 Stockholm, Sweden
(Received August 21, 2000)
(Accepted in revised form December 18, 2000)
Keywords: Nanoparticles; Superparamagnetism; MRI; in-vivo; Brain; Contrast agent
Introduction
The recent development of functionalized nanoparticles is expected to bring a break-through to the
possibilities in several biomedical application, e.g. targeted drug delivery, tissue engineering, MRI
techniques as well as monitoring mental or neurodegenerative diseases. The aim of the present
investigation is to design target specific markers that can be used for detecting morphological and
physiological changes in vivo using magnetic resonance imaging (MRI) technique. Processes in the
tissue where the blood brain barrier is intact in this way shielded from the contact to this conventional
contrast agent and will only reveal changes in the tissue if it involves an alteration in the vasculature.
This technique is very useful for detecting tumors and can even be used for detecting metabolic
functional alterations in the brain such as epileptic activity [1]. The Volume Transmission phenomenon
also shows that there are very well developed and efficient systems for transporting and distributing
compounds present in the extracellular compartment. This endogenous transport system can be used for
distribution of target specific contrast agents once they are present in the extracellular space of the brain.
In this paper, we have tried the biocompatibility in vivo treatments and MR sensitivity of the core
particles consisting of superparamagnetic iron oxide nanoparticles.
Experimental Procedures
The synthesis of magnetite nanoparticles has been carried out via a controlled chemical coprecipitation.
25 ml of iron source was added drop-wise into 250ml of alkali source under vigorous mechanical
stirring (2000rpm) for 30min at room temperature. Two operating conditions, (i) the concentration of
NaOH, and (ii) the pH, were varied for different synthesis experiments. The synthesized nanoparticles
of Fe
3
O
4
were coated with a surfactant, polyoxyethylene (10) oleyl ether, and left standing in a test tube
over night. The agglomerated larger particles were sedimented and the supernatant colloidal containing
nanoparticles was separated and used for further characterizations and MR imaging studies.
Scripta mater. 44 (2001) 17131717
www.elsevier.com/locate/scriptamat
1359-6462/01/$see front matter. 2001 Acta Materialia Inc. Published by Elsevier Science Ltd. All rights reserved.
PII: S1359-6462(01)00870-3
Results and Discussion
Fig. 1 shows the result of computer-assisted chemical equilibrium calculations of Fe-Cl-H
2
O system,
which were carried out to predict the operating conditions of co-precipitation of the precursor where it
can be protected from undesired critical oxidation during the synthesis process. Based on this modeling
result, a preferable pH and pe values for Fe
3
O
4
precipitation can be predicted at different Fe
2
and Cl

concentration and temperature. Also, we can expect Fe(OH)


3
as a predominant phase under the usual
oxidation conditions such as in air according to this thermodynamic equilibrium diagram. Oxygen
would critically affect the physical and chemical properties of the nanosized magnetic particles. In order
to prevent them from possible oxidation in air as well as from agglomeration, Fe
3
O
4
nanoparticles
produced by reaction were usually coated with organic or inorganic molecules during the precipitation
process. To control the reaction kinetics, which is strongly related with the oxidation speed of iron
species, the present method of flowing N
2
gas is introduced to modify the already published methods
[2].
Using magnetization data, the average sizes of large (D
1
) and small (D
2
) magnetic particles can be
calculated according to Langevins equation, respectively. The size of large particles, which are
oriented at low magnetic field, can be calculated as follows,
D
1

18kT

s
H

dM
dH

H0
(1)
where
s
is the specific magnetisation of the iron oxides, with a value of 89.9 emu/g (Fe
3
O
4
) [3]. The
size of small particles, oriented at a high magnetic field, can be determined as [4]
D
2


6kT

s
H
M
S
M
S
MH

1/3
(2)
Thus, two values of D
1
50 and D
2
27 were obtained for the coated Fe
3
O
4
nanoparticles,
respectively. All methods give a mean particle size of 26 nm, in agreement with the value for
Figure 1. The pH-pe predominance diagram of Fe-Cl-H
2
O system at 25C.
SUPERPARAMAGNETIC IRON OXIDE 1714 Vol. 44, Nos. 8/9
superparamagnetic Fe
3
O
4
nanoparticles as reported by others [4]. Differences between the particle size
determined by TEM and that by magnetization measurements, can be assumed to be due to the
surfactant layer coated on Fe
3
O
4
particles. The thickness is thus 12 nm. The surfactant-coated layer
can be considered as a magnetically dead layer at the surface, thus affecting the uniformity or magnitude
of magnetization due to quenching of surface moments.
The magnetic field dependence of the magnetization of coated Fe
3
O
4
nanoparticles is shown Fig. 2.
Above the blocking temperature (T
B
), the thermal fluctuation energy (k
B
T) is larger than the uniaxial
anisotropy energy (KV) because the critical volume is larger than magnetic moment of all particles sizes
for that temperature are magnetically frozen along their anisotropy axes. The high temperature regime,
assuming it as an equilibrium state, the magnetic susceptibility follows a Curie-Weiss law [5].
For MRI studying, two procedures were used for administrating the particles. The first procedure
was carried out outside the magnet and the recording was performed one hour after injection. The
second procedures in the scanner recording were made during the injection and repeatedly thereafter.
Procedure one: The well anaesthetized rat was adapted in a stereotaxic frame and a small hole, 0.5 mm
in diameter, was made in the skull bone using a dental drill. The bone was gently removed and the dura
mater was free visible without any haemorrage. A small glass micro capillary pipette was stereotaxi-
cally inserted through the dura mater into the superficial layer of brain parenchyma and into the dorsal
part of hippocampus. The capillary was filled with the iron oxide particle solution and connected to a
micro syringe before inserted into the brain. A volume of 1 l was injected at a speed of 1 l per min
and the pipette was thereafter slowly retracted during one minute. In the other procedure the glass
capillary was fixed in position to the skull bone by dental cement. As soon as the cement was dry the
rats were transferred to a MR compatible, purpose built, stereotaxic holder and positioned in the MR
scanner for recording. The location of the capillary was traced using a number of scout images and a
coronal slice was placed through the tip of the capillary before injection.
Figure 2. Magnetization vs applied magnetic field for Fe
3
O
4
nanoparticles coated with polyoxyethylene (10) oleyl ether.
SUPERPARAMAGNETIC IRON OXIDE 1715 Vol. 44, Nos. 8/9
In Fig. 3, the images of Panel B were recorded using the same parameters as those of panel A but
one hour after the injection. The superparamagnetic Fe
3
O
4
nanoparticles interfered in such a way that
the signal intensity was decreased to zero, shown as a black region on the images. As seen, Fe
3
O
4
nanoparticles spread into the ventricular system, especially in the lateral ventricles shown by the images
B1 and B2 in Fig 3. The images of Panel C were recorded at the same position as A and B but using
a gradient echo sequence instead which enhance the susceptibility effect from the injected nanopar-
ticles. This effect in this case was so strong that the morphology was lost in the image. When spinning
magnet of Fe
3
O
4
nanoparticles was placed in a strong magnetic field, it started processing around it just
as a spinning top processes about the vertical axis before falling. The fluid in rat brain was detected by
making the hydrogen nuclei present in the water molecules under strong magnetic field. The intensity
difference of energy radiation between fluid in rat brain and injected superparamagnetic Fe
3
O
4
nanoparticles was shown by different darkness in images.
Conclusion
Nonionic surfactant (polyoxyethylene (10) oleyl ether) coated superparamagnetic Fe
3
O
4
nanoparticles
with narrow size distribution were prepared by chemical coprecipitation method as a diagnostic tracer
for MRI imaging. The MRI results have indicated that these nanoparticles have a superparamagnetic
property that is detectable in an MRI scanner, thus to be a suitable substrate for MR contrast agents.
Furthermore, the small size of the nanoparticles makes it possible for them to be selectively transported
through, or target to, the nanosized intercellular space in the living brain. Thus, these results open the
possibility for using these superparamagnetic Fe
3
O
4
nanoparticles as selective MRI contrast agents or
in drug delivery.
Acknowledgments
This work has been supported by Swedish Foundation for Strategic Research (SSF-6711) and Swedish
Research Council for Engineering Sciences (TFR).
Figure 3. The three panels show the rostro-caudal projection of coronal slices true the rat brain before injection (panel A) and
one hour after injection of 1 l of Fe
3
O
4
nanoparticles (panel B) visualized by using a RARE sequence and in panel C using a
GEFI sequence. The dark regions in the brain indicate the localization of the iron particles.
SUPERPARAMAGNETIC IRON OXIDE 1716 Vol. 44, Nos. 8/9
References
1. T. Reese, B. Bjelke, R. Porszasz, D. Baumann, D. Bochelen, A. Sauter, and M. Rudin, NMR Biomed. 13, 43 (2000).
2. Y. S. Kang, S Risbud, J. F. Rabolt, and P. Stroeve, Chem. Mater. 8, 2209 (1996).
3. S. Chikazumi, in Physics of Magnetism, ed. J. Wilely. p. 100, Krieger (1964).
4. R. Massart, IEEE Trans. Magn. MAG-17, 1247 (1981).
5. G. A. Sawatsky, F. van der Woude, and A. H. Morrish, J .Appl. Phys. 39, 1204 (1968).
SUPERPARAMAGNETIC IRON OXIDE 1717 Vol. 44, Nos. 8/9

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