Article
pubs.acs.org/Langmuir
Mesoscale Assemblies of Iron Oxide Nanocubes as Heat Mediators
and Image Contrast Agents
Maria Elena Materia,† Pablo Guardia,† Ayyappan Sathya,† Manuel Pernia Leal,† Roberto Marotta,†
Riccardo Di Corato,†,‡ and Teresa Pellegrino*,†
†
Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy
National Nanotechnology Laboratory of CNR-NANO, via per Arnesano km 5, 73100 Lecce, Italy
‡
S Supporting Information
*
ABSTRACT: Iron oxide nanocubes (IONCs) represent one
of the most promising iron-based nanoparticles for both
magnetic resonance image (MRI) and magnetically mediated
hyperthermia (MMH). Here, we have set a protocol to control
the aggregation of magnetically interacting IONCs within a
polymeric matrix in a so-called magnetic nanobead (MNB)
having mesoscale size (200 nm). By the comparison with
individual coated nanocubes, we elucidate the effect of the
aggregation on the specific adsorption rates (SAR) and on the
T1 and T2 relaxation times. We found that while SAR values decrease as IONCs are aggregated into MNBs but still keeping
significant SAR values (200 W/g at 300 kHz), relaxation times show very interesting properties with outstanding values of r2/r1
ratio for the MNBs with respect to single IONCs.
heterostructures made of different magnetic materials.11 The
manipulation of MNPs and their aggregation into controlled
clusters could play a significant role on the heating performance
of nanoparticles. The relation between the heating performance
and the aggregation state of MNPs remains an open question.
An improvement in the heating performance while aggregating
MNPs has been recently reported.12 Nonetheless, an opposite
trend has been observed when increasing the magnetic
interaction between nanoparticles by increasing the concentration.13 A similar disagreement can be also found in the
reported theoretical studies.14 Moreover, this also depends if
superparamagnetic, ferromagnetic or nanoparticles at the
interface between superpara- and ferromagnetism are taken
into consideration. Such a controversy calls for a direct
comparison between a single dispersed and a controlled
aggregated system made of the same MNPs, especially if the
individual nanoparticles have high SAR values. Indeed, this has
been one of the purposes of this work.
On the other hand, MNPs are also exploited as contrast
agents for MRI diagnosis. Owing to their intrinsic properties,
they are able to induce strong magnetic field inhomogeneities,
which translate into a higher contrast wherever they
accumulate, for instance to the tumor areas.15,16 The MRI
signal intensity does solely depend on the relaxation of the net
magnetization of a proton under a static magnetic field. Under
the influence of an external magnetic field an excited proton
can relax along longitudinal (T1 or spin−lattice) or trasversal
1. INTRODUCTION
Inorganic nanocrystals provide novel tools to address the
challenges of current medicine1 including drug delivery,2
detection,3 imaging,4 and hyperthermia applications.5 The
concept of magnetic mediated hyperthermia (MMH) relies
on the generation of heat via an oscillating magnetic field
exploiting magnetic nanoparticles (MNPs) as heat mediators.
Under heat, damages are then induced in cancer cells, these
being more sensitive than healthy cells to temperatures higher
than 41 °C.6 The combination of MMH with conventional
therapies, such as chemotherapy or radiotherapy, has proven to
be more effective in the treatment of glyoblastoma, a very
malignant brain tumor.7 The heating efficiency of a heat probe
is evaluated by its specific absorption rate (SAR) value, which
provides the power absorbed per unit mass of magnetic
material (W/g) when exposed to an alternating magnetic field
(AMF). The SAR value of a given MNP does strongly depend
on the size, shape, structure of the nanoparticle as well as the
frequency ( f) and the amplitude of the magnetic field (H)
applied.5a,8 Some medical constraints are imposed to the
physical parameters of the AMF for a safe application of
hyperthermia to patients as indeed the product of the frequency
and the magnetic field amplitude (Hf) cannot exceed a certain
threshold (5 × 109 Am−1s−1).9 Clinical experiments on patients
have been carried out without any harm at 110 kHz and 10−20
kAm−1. This issue imposes some limitations to the hyperthermia treatment and at the same time pushes toward the
development of more suitable and efficient MNPs under these
physical conditions. Outstanding SAR values have been
achieved by synthesizing cubic-shaped nanocrystals of iron
oxides, like the ones used in this study,10 or by preparing
© 2015 American Chemical Society
Received: October 6, 2014
Revised: December 13, 2014
Published: January 8, 2015
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(T2 or spin−spin) directions.17 Superparamagnetic iron oxide
nanoparticles are able to shorten the T2 relaxation time (or
increase r2), resulting in a reduction in MRI signal intensity
(negative contrast).18
The efficiency of a contrast agent does also depend on the
surface chemistry, size, shape, and aggregation state of the
magnetic nanoparticles. The influence on r2 relaxivity of
magnetic clusters made up of spherical and superparamagnetic
nanoparticles with different size was studied systematically by
several groups.19
Meso- or submicrometer three-dimensional structures of
multiple magnetic nanoparticles could be obtained by disparate
procedures.20 Spherical nanoclusters of MNPs embedded in
polymer matrix, also known as magnetic nanobeads (MNBs),
are among the most common clusters that can be produced,20
and their surface can be functionalized toward cancer
targeting.20d Also, the easy synthesis allows to include
fluorescent nanoparticles or dye molecules within the same
bead, making the MNBs promising as multifunctional platforms
for biomedical applications.20b,21
Also, the outstanding performances of ferromagnetic IONCs
of 30 nm as T2 contrast agent22 were recently reported.
However, less is known about the r1 and r2 values of clusters of
magnetic nanocubes which show magnetic properties at the
transition between superpara- and ferromagnetic behavior.
For performing our study, the key was to set a protocol to
obtain nanobeads using highly interacting magnetic nanocubes.
We did succeed, and we found that the aggregation of IONCs
into MNBs of 200 nm in size decrease the SAR values, but still
keeping significant heat performances for hyperthermia treatment. The absolute values of r1 and r2 relaxation times decrease
for the MNBs; however, the r2/r1 ratios are higher compared
with those of IONCs.
Scheme 1. Preparation of Water Soluble IONCs (a) and
MNBs (b)a
Starting from the same hydrophobic IONCs (23 ± 3 nm), IONCs
are transferred in water by mixing the hydrophobic IONCs in toluene
with the gallol-bearing PEG ligand (GA-PEG-OH) in the presence of a
base (1a). The solution is shaken for a few seconds, and after acetone
addition, the PEG-IONCs are extracted in water (2a). Finally, after
organic solvent evaporation at reduced pressure, the PEG-IONCs
solution is dialyzed to remove the excess of GA-PEG-OH (3a). This
protocol provides the single coated nanocubes in water. The MNBs
instead are obtained by mixing the hydrophobic IONCs with a
poly(maleic anhydride-alt-1-octadecene) polymer (PC18), in CHCl3
(1b). The solution is shaken for few seconds, and then 1 mL of
acetonitrile is added at a flow rate of 2 mL min−1 (2b). The MNBs are
collected by magnetic sorting and redissolved in water (3b).
a
were injected. The mixture was diluted with 50 mL of toluene, shaken,
and transferred in a separating funnel. Then, 250 mL of deionized
water was added, resulting in a two-phase mixture that was gently
shaken. After the ligand exchange took placed, the IONCs were laid at
the toluene−water interface. To drive the nanoparticles into the
aqueous phase, 50 mL of acetone was added in order to destabilize the
particles from the organic phase and drive them quantitatively into the
aqueous phase. After emulsification by means of shaking, the phases
were allowed to separate and the aqueous phase containing the IONCs
bearing GA-PEG-OH was collected. This step was repeated until all
the IONCs were transferred into water, and the organic phase was
completely transparent. After concentrating them into a total volume
of 10 mL under reduced pressure (300 mbar for 30 min, 200 mbar for
30 min, 77 mbar for 30 min, and 10 mbar for 10 min) at 40 °C, the
excess of GA-PEG-OH was removed by dialysis versus deionized water
using membrane filters with molecular cutoff point of 50 kDa. The
sample was left in dialysis for 2 days at room temperature. Finally, the
IONCs solution was concentrated by centrifugation (6.6 g/L of Fe) in
a centrifuge filter (molecular cutoff point 100 kDa), and the recovered
solution of IONCs was analyzed by DLS and TEM.
2.4. Synthesis of MNBs. The synthesis of MNBs used is based on
a previous reported work with substantial modifications.20d Briefly, to
prepare MNBs of IONCs, in an 8 mL glass vial, 36.5 μL of IONCs
(0.12 μM nanoparticles concentration, d = 23 ± 3 nm) in chloroform
was sonicated for few minutes. Soon after, 78.5 μL of chloroform and
then 10 μL of a stock solution of poly(maleic anhydride-alt-1octadecene) (PC18) in CHCl3 (50 mM, this concentration refers to
the polymer monomer units) were added. The mixture was sonicated
again for 1 min and then shaken in an orbital shaker (Multi Reax,
Heidolph) at 1250 rpm for 30 s at 20 °C. Subsequently, 1 mL of
acetonitrile (ACN) was added at a flow rate of 2 mL min−1. To
transfer the MNBs in water, the MNBs were quantitatively collected
by keeping them on top of an external magnet (0.3 T) for about 10
2. EXPERIMENTAL SECTION
2.1. Materials. Poly(maleic anhydride-alt-1-octadecene), PC18,
Mn 30 000−50 000 (Aldrich), Milli-Q water (18.2 MΩ, filtered with
filter pore size 0.22 μM) from Millipore, boric acid (Sigma-Aldrich,
99%), sodium tetraborate decahydrate (Sigma-Aldrich, ≥99.5%),
acetonitrile (HPLC grade, J.T. Baker), chloroform (Sigma-Aldrich,
99%), iron(III) acetylacetonate (Acros Organics, 99%), decanoic acid
(Acros Organics, 99%), dibenzyl ether (Acros Organic, 99%), squalane
(Alfa Aesar, 98%), diethylene glycol Reagent Plus (Sigma-Aldrich,
99%), and poly(ethylene glycol) Mn 380−420 (Sigma-Aldrich). All
chemicals were used without any further purification.
2.2. Synthesis of Iron Oxide Nanocubes (IONCs) and
Magnetic Nanobeads (MNBs). Synthesis of 23 ± 3 nm IONCs.
IONCs were synthesized by using a previous reported procedure.23
Briefly, in a 50 mL three-neck flask 0.353 g (1 mmol) of iron(III)
acetylacetonate with 0.69 g (4 mmol) of decanoic acid and 18 mL of
dibenzyl ether were dissolved in 7 mL of squalane. After degassing for
120 min at 65 °C, the mixture was heated up to 200 °C (3 °C/min)
and kept at this value for 2.5 h. Finally, the temperature was increased
at a heating rate of 7 °C/min up to 310 °C or reflux temperature and
maintained at this value for 1 h. After cooling down to room
temperature, 60 mL of acetone was added, and the whole solution was
centrifuged at 8500 rpm. After removing the supernatant, the black
precipitate was dispersed in 2−3 mL of chloroform, and the washing
procedure was repeated at least two more times. Finally, the collected
particles were dispersed in 15 mL of chloroform.
2.3. Transfer in Water of IONCs. To transfer IONCs into water,
a ligand exchange procedure was used by using a gallic-functionalized
poly(ethylene glycol) (GA-PEG-OH) molecule whose synthesis was
previously reported (Scheme 1).23,24 To a 5 mL stock solution of
IONCs (concentration 1.9 g/L of Fe in CHCl3), 10 mL of the ligand
GA-PEG-OH solution (0.05 M in CHCl3) and 1 mL of triethylamine
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CryoEM Analysis. Frozen hydrated samples were prepared by dropcasting a 3 μL of sample aliquot on 200-mesh Quantifoil holey carbon
grids previously glow discharged (Ted Pella). Before plunging into
liquid ethane, the grids were blotted for 1.5 s in a chamber at 4 °C and
90% humidity using a FEI Vitrobot Mark IV (FEI). The nanoparticles
were imaged with a 2k × 2k US 1000 Gatan CCD camera using a
Tecnai G2 F20 transmission electron microscope (FEI), equipped
with a field emission gun operating at an acceleration voltage of 200
kV.
Dynamic Light Scattering (DLS) Characterization. Dynamic light
scattering measurements were performed on a Zetasizer Nano ZS90
(Malvern) equipped with a 4.0 mW He−Ne laser operating at 633 nm
and an avalanche photodiode detector. Measurements were conducted
with a ZEN0112-low volume disposable sizing cuvette, setting 1.330 as
the refractive index and 0.8869 cP as the viscosity. The measurements
were performed with 173° backscatter (NIBS default) as angle of
detection, with an automatic scan time and three scans per
measurement.
SQUID Characterization. Magnetization curves at 5 and 300 K
were measured in the range from −70 to +70 kOe by using a
superconducting quantum interference device (SQUID) from
Quantum Design MPMS. Thermal dependence of the magnetization
was also measured in zero field cooling (ZFC) and field cooling (FC)
runs by applying a cooling field of Hcooling = 100 Oe and a magnetic
field of Hmeas = 100 Oe during the measurement. For the
measurements, 150 μL of a solution of IONCs and MNBs was
dried on a Teflon film and measured. The mass normalization was
done by elemental analysis of the Teflon film.
min. The supernatant was then removed, and the MNBs were
dissolved in 500 μL of borate buffer solution (pH 9). To completely
solubilize the MNBs, it was necessary to sonicate and warm up (∼40
°C) the sample solution for a few minutes. The MNBs were collected
again to the magnet and then redissolved in 500 μL of Milli-Q water.
To have enough materials for SAR measurements, the above-reported
procedure was repeated 100 times. The MNBs from each batch were
recovered to the magnet and redissolved in the same volume of water.
The final concentration of MNBs was adjusted to 5.5 g/L of Fe.
2.5. Hyperthermia Measurements on IONCs and MNBs. All
the measurements were carried out in a commercially available DM100
Series (nanoScale Biomagnetics Corp.) setup. For example, to evaluate
the SAR of the IONCs in water (6.6 g/L of Fe), 100 μL of sample was
introduced into a sample holder and exposed under an ac magnetic
field at two different frequencies (110 and 300 kHz) under magnetic
field amplitudes up to 24 kA m−1. Afterward, 100 μL of a fresh solution
of IONCs was added to a 4 mL vial and placed under a magnet until
all MNPs were collected at the bottom of the vial. Then the
supernatant was removed, and IONCs were redissolved in 100 μL of
diethylene glycol (DEG) obtaining concentrations of 6.6 g/L of Fe.
The same procedure was performed for poly(ethylene glycol) 400
(PEG400) and the final concentration of IONCs adjusted to 7.4 g/L
of Fe. Following the same procedure, three solutions of 100 μL of
MNBs dispersed in water (5.5 g/L of Fe), DEG (6.2 g/L of Fe), and
PEG400 (5.7 g/L of Fe) were prepared and used for the SAR
measurements.
All reported SAR values and error bars were calculated from the
mean and standard deviation, respectively, of at least four experimental
measurements. SAR values were calculated according to the equation
⎛W⎞
C dT
SAR ⎜ ⎟ =
m dt
⎝g⎠
3. RESULTS AND DISCUSSION
Synthesis of IONCs and MNBs. As reported in Scheme 1,
the same batch of hydrophobic IONCs (23 nm, edge length)
was used for preparing either the clusters (MNBs) or the watersoluble single IONCs. For the preparation of water-soluble
IONCs it is required the use of suitable ligands which allow, in
a polar solvent, to replace the hydrophobic surfactant molecules
at the nanoparticle surface and introduce a thin coating shell
that avoids interparticle coalescence. The synthesis of MNBs is
a one-step procedure and is based on the clustering of
hydrophobic IONCs within a polymer shell with several
entangled variables that control the cluster formation (Scheme
1). For the water transfer of hydrophobic IONCs we applied a
protocol reported by us, which makes use of catechol derivative
PEG molecules.23,24 For the MNBs our well-established
protocol for superparamagnetic nanoparticles had to be
substantially modified as here we used strongly interacting
magnetic nanoparticles at the interphase between superparaand ferrimagnetism.
For example, in our previous reports,20d,21,25 particles were
always transferred from toluene to tetrahydrofuran (THF)
before adding the polymer. This involves a solvent drying step
which for the case of IONCs always let to a strong aggregation.
Indeed, following this procedure with the nanocubes, MNBs
with size at micrometer scale and a broad size distribution were
obtained (data not shown). Moreover the IONCs are not well
soluble in THF. For the synthesis of smaller clusters, we
avoided this solvent evaporation step by directly adding both
IONCs and polymer in the same solvent (both IONCs and the
polymer are fully soluble in CHCl3). Besides, we also observed
that after the addition of the polymer a sonication step
improves the formation of MNBs below 200 nm although
never smaller than 150 nm with a relative narrow size
distribution. The second step involves the destabilization of
IONCs and polymer by the addition of a more polar solvent.
We chose acetonitrile (ACN) as destabilizing agent as it is fully
where C is the specific heat capacity of the solvent (Cwater = 4185
JL−1K−1, CDEG = 2584 J L−1 K−1, and CPEG400 = 2171 J L−1 K−1) and m
is the concentration (g/L of Fe) of magnetic material in solution. Note
that the final values are reported as (W/gFe). The measurements were
carried out in nonadiabatic conditions; thus, the slope of the curve dT/
dt was measured by taking into account only the first few seconds of
the curve.
2.6. Relaxivity Measurements. Water solutions of IONCs and
MNBs solution containing different Fe concentration ranging from
0.001 to 2 mM were prepared. The longitudinal (T1) and transverse
(T2) relaxation times were measured at 40 °C using a Minispec
spectrometer (Bruker, Germany) mq 20 (0.5 T), mq 40 (1 T), and mq
60 (1.5 T). The T1 relaxation profile was obtained using an inversion−
recovery sequence, with 20 data points and four acquisitions for each
measurement. T2 relaxation time was measured using a Carr−Purcell−
Meiboom−Gill (CPMG) spin-echo pulse sequence with 200 data
points with interecho time of 0.5 ms. The relaxivities ri (i = 1, 2) were
determined by the equation
1
1
=
+ rC
i Fe
Ti(obs)
Ti(H2O)
(i = 1, 2)
where CFe is the concentration of Fe ions. The values are reproducible
within 5% deviation.
2.7. Structural and Elemental Characterization. Elemental
Analysis. An inductively coupled plasma atomic emission spectrometer
(ICP-AES, iCAP 6500, Thermo) was used for the elemental analysis
and concentration evaluation of IONCs and MNBs. The samples were
prepared by overnight digestion of 25 μL of nanoparticles solution in
2.5 mL of aqua regia. Subsequently, the sample was diluted with
deionized water to a final volume of 25 mL.
TEM Characterization. Transmission electron microscopy was
carried out on a JEOL JEM-1011 with an acceleration voltage of 100
kV. The sample preparation was conducted by drop-casting a droplet
of the sample solution onto a carbon-coated copper grid with
subsequent removal of the solvent by evaporation at room
temperature.
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When looking at the TEM images of nanobeads at lower
magnification (Figure 1D), a mixture of spherical and
anisotropic nanobeads of nanocubes was obtained. Given the
restricted window of conditions that can be modified to obtain
beads of nanocubes, control over the thickness of the polymer
shell, of the shape of the MNBs, and the distribution of
nanocubes within the beads is rather poor. With the aim to
obtain more anisotropic structures, we also attempted to
perform the bead protocol in the presence of a small magnet
(0.2−0.1 T) placed beneath the vial during the bead formation.
A similar procedure was previously exploited by us to arrange
spherical superparamagnetic nanoparticles into submicrometer
magnetic rod assemblies.26 Nonetheless, for nanocubes this
resulted in a massive precipitation during the bead formation
(data not shown). Likely the magnet attracts nanocubes as well
as increases the magnetic interaction between them inducing an
uncontrolled aggregation with consequent loss of control over
the MNBs formation. Nevertheless, on the obtained samples of
MNBs and IONCs as in Figure 1 the comparative magnetic
studies could be carried out.
Hyperthermia Performance of IONCs and MNBs. In
Figure 2, the SAR values measured at two different frequencies
(300 and 110 kHz) and magnetic field amplitudes (in the range
between 12 and 24 kAm−1) reveal that MNBs always have a
lower heating performance compared to IONCs for all the
tested conditions. For instance, the maximum SAR value was
measured at 300 kHz and 24 kAm−1, and for IONCs it was up
to 382 ± 4 W/gFe with respect to 193 ± 9 W/gFe for MNBs.
The decrease in SAR values might be likely attributed to the
magnetic interaction between very close nanocubes within the
clusters. This is in close agreement with the results reported by
Martinez-Boubeta et al. in which the SAR value decreases while
increasing the nanoparticle concentration and thus the
magnetic dipole−dipole interaction.13 Our results also fit the
SAR values estimated by simulations performed by different
other groups,14a,c,d which also predict that the heating
performance decreases as the magnetic dipole−dipole interactions increase. However, the comparison of our MNBs to
those might be not completely appropriate.
Unfortunately, only few studies have measured the SAR
values on nanoparticle clusters. Hyeon and co-workers for
instance, when setting protocols to solubilize 30 nm IONCs in
water, have synthesized small clusters made of IONCs within a
shell of dextran.12a Besides the difference in the DLS diameter
between our clusters and their samples which have a diameter
around 103 ± 15 nm, the dextran clusters have a rather 2D
organization (usually 4−10 particles per bead) compare to our
clusters which are made of many more nanocubes arranged in a
3D object (20−30 nanocubes per bead). This might account
for the difference in the heating performance between our
clusters and their clusters. Indeed, in contrast to our data,
significant higher SAR values were measured on Hyeon’s
clusters. Moreover, in our case we do work with 23 nm cubes
which are at the interface between superparamagnetic and
ferrimagnetic nanoparticles while the chitosan clusters were
made of ferrimagnetic 30 nm nanocubes. On the other hand,
the lack of SAR values for single 30 nm cubes does not allow us
to compare our results with these single IONCs. In another
SAR study based on chitosan cluster of superparamagnetic iron
oxide nanoparticles of about 5 and 9 nm in diameter, the
authors reported larger heat dissipation for the more interacting
nanoparticles assemblies.27 In comparison to our MNBs,
nanoparticles appear to be well separated within the clusters.
miscible with CHCl3 and has a higher polarity than CHCl3, a
condition necessary for inducing aggregation (in comparison,
the standard method uses a single phase of THF/ACN).
As a further modification to the MNB procedure, while in the
previous method the addition rate of the ACN/THF solution
was 0.25 mL min−1, here we had to increase the rate up to 2 mL
min−1. We observed that at slow addition rates IONCs tend to
aggregate faster which leads to bigger beads with large size
distribution (see Figure S1 in the Supporting Information). In
general, one can assume that the bead formation is a two-step
process in which first the nanoparticle aggregation occurs
followed by a stabilization step which consists of polymer
enwrapping of the preformed aggregates. The addition of ACN
to CHCl3 changes both the solubility of the IONCs and that of
the polymer. However, due to stronger magnetic interactions,
IONCs tend to aggregate very quickly upon ACN addition.
Thus, a fast injection of ACN is required to induce a quick
polymer destabilization over the clusters thus avoiding the
massive precipitation of the nanocube clusters in macroscopically aggregates. Upon collection of the MNBs to the magnet
and subsequent redispersion in water, the hydrolysis of the
anhydride groups provides negative charges to the polymer
bead surface and hence colloidal stability in water by charge
repulsion. Figure 1 shows the TEM and cryoTEM images of
Figure 1. TEM (A, B) and cryoEM images (C, D) of water-soluble
IONCs (average size = 23 ± 3 nm) and IONCs based MNBs taken on
an air dried sample deposited on the TEM grid (A, B) and on samples
in their frozen hydrated state (C, D). DLS hydrodynamic diameters on
IONCs and MNBs (E). Inset: average hydrodynamic sizes; the
polydispersion index (PdI) is 0.15 and 0.09 respectively for IONCs
and MNBs.
the obtained PEG-coated IONCs of 23 ± 3 nm (as measured
by TEM) and polymer-coated MNBs of 173 ± 25 nm in size
together with their respective DLS hydrodynamic diameters
which have low polydispersion indexes (PDIs) (see also Figure
2S for DLS spectra of the MNBs plotted by intensity and
volume). Worthily, cryoTEM images (Figures 1C and 1D)
recorded on frozen solutions of IONCs or MNBs capture the
images of both samples in their hydrated state and just suggest
that both nanocubes and beads were individually coated by the
polymer layers and appeared as well distinct entities.
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Figure 2. Measured SAR values as a function of the magnetic field amplitude H for water-soluble IONCs (A) and MNBs (B) at 300 kHz (black
empty circles) and 110 kHz (green empty triangles). SAR values as a function of the product Hf for water-soluble IONCs (C) and MNBs (D) at 12
kA m−1 (red rhombi), 16 kA m−1 (green triangles), 20 kA m−1 (blue squares), and 24 kA m−1 (black circles). Each experimental data point was
calculated as the mean value of at least three measurements, and error bars indicate the standard deviation. Dashed lines are drawn to guide the eyes.
The vertical dashed line defines the biological limit (5 × 109 A m−1 s−1).
Figure 3. SAR values as a function of the magnetic field amplitude H (kAm−1) and the viscosity (mPa·s) at 300 kHz for IONCs (A) and MNBs (B)
and at 110 kHz for IONCs (C) and MNBs (D). Each experimental data point was calculated as the mean value of at least three measurements.
In addition, the difference in size definitively plays a role on the
strength of the magnetic dipole−dipole interaction. It is worthy
to mention that simulations on the hyperthermia performance
of magnetic nanoparticles and their clusters have shown a
similar disagreement.14
We also underline that while our results clearly point out to a
decrease in the heating performance as particles get aggregated,
it is worthy to keep in mind that our MNBs are pseudospherical
aggregates. Anisotropic aggregates could have completely
different behavior.14b For example, the heat performance of
magnetosomes, a chain-like structure of iron oxide nanoparticles of about 35−50 nm naturally produced by magnetotactic bacteria, are among the best so far reported.28 However,
in a magnetosome chain, each magnetite crystal is enwrapped
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Table 1. Relaxivities (r1, r2) and r2/r1 of IONCs and MNBs under Different Frequencies
20 MHz
40 MHz
relaxivity (mM−1 s−1)
60 MHz
relaxivity (mM−1 s−1)
relaxivity (mM−1 s−1)
sample
RH (nm)
r1
r2
r2/r1
r1
r2
r2/r1
r1
r2
r2/r1
IONCs
MNBs
47.5
175
39.3
2.25
317
162
8
72
24.2
1.3
398
146
16.4
113
7.7
0.65
260.3
130.3
33.8
200
Figure 4. r1, r2, and r2/r1 ratio as a function of the applied magnetic field for individual IONCs (A) and MNBs (B).
within a lipid bilayer which keep the MNPs well separated.29
Since the magnetic dipole−dipole interaction follows an inverse
cubic law with the distance, the distance between crystals in
magnetosomes might result in a weak magnetic dipole−dipole
interaction and has to be taken into account. On top of it, also
the shape and colloidal anisotropy contribution of the chain
might be responsible for the higher heating performance of
magnetosomes. Efforts need to be devoted to clarify this point,
but so far direct comparison between chain and single
magnetosomes has not been reported, likely because obtaining
single magnetosomes is challenging.
The SAR values for our IONCs and MNBs were also
measured when dissolving the samples in more viscous solvents
(DEG and PEG400). As reported in Figure 3, SAR values
decrease while the viscosity (η) increases, showing a much
more significant effect on the MNBs than on single IONCs.
This trend was observed at both frequencies and magnetic field
amplitudes. One could recall that the power dissipation during
a hyperthermia experiment results from the contribution of two
relaxation processes: Brownian relaxation (PR) and hysteresis
losses (PH).6b,8a In this regard, for both samples the SAR values
decrease while increasing the viscosity which could be
attributed to the suppression of the Brownian relaxation
process.8a,30 The absolute decrease in SAR values is however
higher for MNBs than for the single IONCs underlining a
stronger Brownian contribution for the MNBs. Indeed, the
Brownian relaxation time is directly proportional to the
hydrodynamic volume of the probe and the DLS diameter of
the MNB is bigger than that of a single nanocube.
When comparing the SARs obtained in solvents at different
viscosity (Figure 3 and Figures S5−S10), it could be also seen
that in the case of single nanocubes there is no further decrease
in the SAR values when the viscosity increases (from DEG to
PEG400). This suggests that the Brownian contribution to the
SAR is completely suppressed already in DEG being the
nanocubes smaller in hydrodynamic diameters. On the
contrary, MNBs showed a progressive drop of the heating
performance as viscosity increases. This trend points out to a
stronger dependence of the heating performance of MNBs with
viscosity and hence to a more significant contribution of the
Brownian relaxation. This might be explained by a different
heating process compared with IONCs. Indeed, as above
reported, aggregation of IONCs might compromise the
contribution of hysteresis losses to the heating performance,
thus increasing that of Brownian relaxation. Finally, it is also
worthy to underline the different magnetic behavior between
IONCs and MNBs (Figures S3 and S4). Saturation magnetization values at 5 and 300 K are lower for MNBs, in addition
to a lower initial susceptibility at both temperatures for the
MNBs with respect to IONCs. These differences support the
lower SAR values of MNBs with respect to IONCs.
Relaxivity of IONCs and MNBs. In order to achieve high
sensitivity in magnetic resonance imaging, it is crucial to
shorten the relaxation time of tissue protons by using proper
magnetic contrast agents.31 The T1 (spin−lattice) relaxation
process is an outcome of the dissipation of an excited proton to
its surrounding environment whereas the T2 (spin−spin)
relaxation process involves the interaction between the excited
nuclei and those with lower energy level. Increasing r2/r1 ratio
plays a key role in improving the darker signals or T2-weighted
images in MRI (when the r2/r1 is greater than 2, the
nanoparticles are better for T2 contrast agent for MRI.).32
Table 1 and Figure 4 show the measured r1, r2, and r2/r1 ratio
(see also Figure S11). The absolute r2 values of IONCs under
0.5−1.5 T field are about 398−260 mM−1s−1. The relaxivity
values for IONCs are comparable with the literature report on
iron oxide nanocubes.22a Similarly, the r2 values of our MNBs
exhibit about 161 and 130 mM−1 s−1, which is higher than the
reported values of similar size nanoclusters that are made up of
spherical superparamagnetic iron oxide particles.33 We ascribe
the high r2 value of IONCs compared to MNBs to the higher
saturation magnetization of IONCs (Figure S3). Indeed, spin
relaxation of proton along the transverse direction (r2) is much
faster when the magnetic nanoparticles possess high saturation
magnetization.
Further, the hydrodynamic size of the single magnetic
nanocubes is about 47 ± 15 nm, which indicates the IONCs are
in the static diphase region where the r2 values reaches its
highest values. Instead, the aggregation of multiple magnetic
nanocubes and further polymer enwrapping, results in MNBs
with hydrodynamic size of about 173 ± 25 nm with larger size
distribution (Figure 1E). Therefore, MNBs falls in the size
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Langmuir 2015, 31, 808−816
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region of echo limiting region where the r2 value decreases with
increase in size and size distribution.19d The measured r1 values
of MNBs are lower than IONCs in the entire fields. Such
decrease in r1 relaxivity may be due to the different coatings:
While the hydrophobic ligands of IONCs are exchanged with
hydrophilic GA-PEG-OH molecules, MNBs show a thicker
polymer shell formed by the hydrophobic surfactants (decanoic
acid) and the amphiphilic polymer. This extra hydrophobic
layer creates a barrier to the protons; though the water
molecules come near to the nanobeads, the compact hydrophobic decanoic acid restricts the interaction between the water
molecules and IONCs which limits the spin−lattice relaxation
rate and subsequently lowers the r1 of the MNBs.19d,33,34
Nevertheless, both r1 and r2 relaxivities of MNBs are lower
compared to individual IONCs, the r2/r1 ratio of MNBs are
higher and increases dramatically from 72 to 200 with increase
in magnetic field from 0.5 to 1.5 T. These results are in
accordance with the work by Qin et al. 35 A similar
hydrophobic/hydrophilic coating made of PF127 triblock
polymer and the poly(propylene oxide)/oleic acid structure
in their case applied on single superparamagnetic iron oxide
nanoparticles has been exploited to suppress the r1 values and
enhance the r2/r1 value up to 229.35
IONCs and MNBs. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
Corresponding Author
*E-mail: [email protected] (T.P.).
Present Address
M.P.L.: Diagnostic Unit, Andalusiahn Centre for Nanomedicine and Biotechnology, BIONAND, Parque Tecnológico
de Andalucia,́ Málaga, Spain.
Author Contributions
M.E.M. and P.G. have contributed equally to this manuscript.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We are grateful to Simone Nitti and Giammarino Pugliese for
helping with sample preparation. This work was supported by
the European project Magnifyco (Contract NMP4-SL-2009228622) by the EU-ITN network Mag(net)icFun (PITN-GA2012-290248) and by the Italian FIRB projects (Nanostructured oxides, contract no. 588 BAP115AYN).
■
4. CONCLUSIONS
By precisely controlling the synthesis parameters, strongly
interacting IONCs were used as building blocks for the
synthesis of MNBs. Control aggregation into MNBs was
achieved by adjusting the solvent mixture and the injection rate
of the polar solvent (2 mL/min). With respect to the single
IONCs, MNBs show a lower hyperthermia performance due to
the aggregation and hence to an increase of the magnetic
dipole−dipole interactions. The strong decrease of the SAR
values when IONCs were aggregated into a bead structure
matches with both simulations and experiments reported on
magnetic interacting particles. The behavior of the SAR as a
function of the viscosity suggests that the heating processes
involved during a hyperthermia experiment on MNBs and
IONCs are rather different. While energy dissipation in IONCs
is manly governed by hysteresis losses, this could be partially
suppressed in MNBs giving rise to a significant Brownian
contribution to the heating process.
For the relaxivity, although individual IONCs show higher r1
(11−18 times) and r2 (double) values than MNBs, our
nanobeads exhibit very small r1 which in turn corresponds to
high r2/r1 values. These suggest that by making magnetic
nanocubes as clusters, r2/r1 ratio can be increased to a very high
value, which is a key parameter for an efficient T2 contrast
agent.
This comparative study suggests that with such kind of
nanocubes single IONCs have always better SAR and r2
performance than MNBs although when aggregated still the
high r2/r1 values and the measured heat are still exploitable for
theranostic applications.
■
AUTHOR INFORMATION
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ASSOCIATED CONTENT
* Supporting Information
S
TEM images of MNBs samples obtained with two different
acetonitrile addition flow rates; DLS analysis by number,
intensity, and volume for MNBs; SQUID measurements for
IONCs and MNBs; SAR measurements for IONCs and MNBs
in water, DEG, and PEG 400; relaxivities measurements for
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