Composition Tunable Manganese Ferrite Nanoparticles for Optimized T2 Contrast Ability

Article abstract of DOI:10.1021/acs.chemmater.7b00035

Manganese-doped magnetite nanoparticles as magnetic resonance imaging (MRI) contrast agents have been well developed in recent years due to their higher saturation magnetization and stronger transverse (T₂) contrast ability compared to parent magnetite. However, the underlying role that manganese doping plays in altering the contrast ability of magnetite is still not thoroughly understood. Herein, we investigate the effects of manganese doping on changes of ferrite crystal structures, magnetic properties, and contrast abilities. We developed a successful one-pot synthesis of uniform manganese-doped magnetite (Mn_xFe_3-xO₄) nanoparticles with different manganese contents (x = 0-1.06). The saturation magnetization and T₂ contrast ability of ferrite nanoparticles increase along with rising manganese proportion, peak when the doping level of Mn_xFe_3-xO₄ reaches x = 0.43, and decrease dramatically as the manganese percentage continues to augment. At high manganese doping level, the manganese ferrite nanoparticles may undergo lattice distortion according to analysis of XRD patterns and lattice distances, which may result in low saturation magnetization and eventually low T₂ contrast ability. The Mn_xFe_3-xO₄ nanoparticles (x = 0.43) with a diameter of ～18.5 nm exhibit the highest T₂ relaxivity of 904.4 mM^-1 s^-1 at 7.0 T among all the samples and show a much stronger T₂ contrast effect for liver imaging than that of other iron oxide contrast agents. These results indicate that the optimized T₂ contrast ability of manganese ferrite nanoparticles could be achieved by tuning the manganese doping level. This work also opens a new field of vision for developing high-performance T₂ contrast agents by modulating the metal composition of nanoparticles.

Full text of DOI:10.1021/acs.chemmater.7b00035

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Article
Composition Tunable Manganese Ferrite
Nanoparticles for Optimized T2 Contrast Ability
Lijiao Yang, Lengceng Ma, Jingyu Xin, Ao Li, Chengjie Sun, Ruixue
Wei, Bin W. Ren, Zhong Chen, Hongyu Lin, and Jinhao Gao
Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.7b00035 • Publication Date (Web): 16 Mar 2017
Downloaded from http://pubs.acs.org on March 17, 2017
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Composition Tunable Manganese Ferrite Nanoparticles for Optimized
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T2 Contrast Ability
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Lijiao Yang1, Lengceng Ma2, Jingyu Xin1, Ao Li1, Chengjie Sun1, Ruixue Wei1, Bin W. Ren1, Zhong
Chen2, Hongyu Lin1, and Jinhao Gao1*
1State Key Laboratory of Physical Chemistry of Solid Surfaces, The MOE Key Laboratory of
Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian
Province, and iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, China.
2Department of Electronic Science, Fujian Key Laboratory of Plasma and Magnetic Resonance,
College of Physical Science and Technology, Xiamen University, Xiamen, 361005, China
*Email: jhgao@xmu.edu.cn
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ABSTRCT
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Manganeseꢀdoped magnetite nanoparticles as magnetic resonance imaging (MRI) contrast agents
have been well developed in recent years due to their higher saturation magnetization and stronger
transverse (T2) contrast ability compared to parent magnetite. However, the underlying role that
manganese doping plays in altering the contrast ability of magnetite is still not thoroughly
understood. Herein, we investigate the effects of manganese doping on changes of ferrite crystal
structures, magnetic properties, and contrast abilities. We developed a successful oneꢀpot synthesis
of uniform manganeseꢀdoped magnetite (MnxFe3ꢀxO4) nanoparticles with different manganese
contents (x = 0 ~ 1.06). The saturation magnetization and T2 contrast ability of ferrite nanoparticles
increase along with rising manganese proportion, peak when the doping level of MnxFe3ꢀxO4 reaches
x = 0.43, while decrease dramatically as the manganese percentage continues to augment. At high
manganese doping level, the manganese ferrite nanoparticles may undergo lattice distortion
according to analysis of XRD patterns and lattice distances, which may result in low saturation
magnetization and eventually low T2 contrast ability. The MnxFe3ꢀxO4 nanoparticles (x = 0.43) with a
diameter of ~18.5 nm exhibit the highest T2 relaxivity of 904.4 mMꢀ1sꢀ1 at 7.0 T among all the
samples, and show a much stronger T2 contrast effect for liver imaging than other iron oxide contrast
agents. These results indicate that the optimized T2 contrast ability of manganese ferrite nanoparticles
could be achieved by tuning the manganese doping level. This work also opens a new field of vision
for developing highꢀperformance T2 contrast agents by modulating the metal composition of
nanoparticles.
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INTRODUCTION
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Magnetite nanoparticles as T2 magnetic resonance imaging (MRI) contrast agents (CAs) have been
wellꢀestablished over the past two decades,1ꢀ4 but its low signal sensitivity is a major limitation and
still not able to meet clinical needs in diagnosis and therapy.5ꢀ7 Researchers have exploited a series of
methods to enhance their contrast abilities in MRI, such as tuning their morphologies and
compositions.8ꢀ11 This strategy has been used for metal doping ferrite MFe2O4 (M = Fe, Co, Ni, and
Mn) nanoparticles as well.12ꢀ14 In Fe3O4 inverse spinel structure, oxide anions form faceꢀcentered
cubic framework, while iron cations occupy part of the interstitial octahedral (Oh) and tetrahedral
(Td) sites.15 Fe3+ cations in Td and Oh sites are antiferromagnetic coupling, which leads to
cancellation of magnetic moments. Consequently, the final magnetic moment of Fe3O4 unit proves to
be the net magnetic moment of Fe2+ cation.16 By replacing Fe2+ (d6) with Mn2+ (d5), Co2+ (d7), or
Ni2+ (d8), the net magnetic moment of MFe2O4 unit can be engineered from 4 ꢁB to 5 ꢁB, 3 ꢁB, or 2
ꢁB, respectively.13 Accordingly, the magnetic properties of MFe2O4 nanoparticles could also be tuned
via replacing Fe2+ with other metal cations fully or partially.
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Magnetic properties of nanoparticles are crucial for their performance in contrastꢀenhanced
MRI.17ꢀ19 According to quantum mechanical outer sphere theory, T2 contrast enhancement is mainly
related to the proton's effective diffusion and interaction with the magnetic dipolar moment: r2 =
(256π2γ2/405) V* Ms2 r2/ D (1+L/a), where Ms is saturation magnetization and r is effective radius of
magnetic nanostructure, D is the diffusivity of water molecules, L is the thickness of an impermeable
surface coating, and V* is the volume fraction, respectively.20ꢀ22 Nanoparticles with higher Ms values
generate stronger local magnetic field inhomogeneity for the water proton dephasing process around
themselves, which accelerates transverse (T2) relaxation of water protons.23 Thus their r2 values are
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highly dependent on their magnetic saturation magnetization. Types and amounts of metal dopants
play a significant role in the magnetic properties of ferrite nanoparticles,24ꢀ25 which can eventually
alter T2 contrast ability. The doping level of metal also has a great effect on crystal structures of
ferrite nanoparticles. For example, Zn2+ ions doping converts the inverse spinel structure of Fe3O4 to
the spinel structure of (ZnxFe1ꢀx)Fe2O4 according to the extended Xꢀray absorption fine structure
(EXAFS) analysis.9 Therefore, the influence of metal dopants on crystal structure and contrast ability
of MFe2O4 nanoparticles needs to be taken into account for the development of nanoparticleꢀbased T2
CAs.
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Among the previously discussed nanoparticles, manganeseꢀdoped magnetite nanoparticles have
the highest magnetic susceptibility owning to the presence of five single unpaired electrons of Mn2+.
Besides, the net magnetic moment of MnFe2O4 unit is 5 ꢁB not matter whether Mn(II) ions occupy
octahedral or tetrahedral sites in the spinel structure of magnetite. As one of the most promising T2
MRI contrast agents in theory, the manganeseꢀdoped magnetite nanoparticleꢀbased CAs have been
developed in recent years.26ꢀ31 Nevertheless, the investigation on the mechanism of the underlying
role that manganese plays in magnetic properties and contrast abilities of magnetite is neglected.
Hence the relationships among manganese doping levels, crystal structures, magnetic properties, and
T2 contrast abilities need to be further clarified.
In this work, we synthesized manganeseꢀdoped magnetite (MnxFe3ꢀxO4) nanoparticles with varied
doping levels using a facile method and investigated their crystal structures, magnetic properties and
contrast abilities. We found that lattice distances and saturation magnetizations of MnxFe3ꢀxO4 are
enlarged gradually with manganese doping level increasing. When the ratio of Mn/Fe reaches to 1/7
(x = 0.43), MnxFe3ꢀxO4 nanoparticles maintained a typical ferrite structure with ultrahigh saturation
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magnetization (Ms) of 89.5 emu/g, which endows them with an extremely strong T2 contrast effect
with an r2 value of 904.4 mMꢀ1sꢀ1 at 7.0 T. When the doping amount of manganese continues to
increase, the crystal structure of MnxFe3ꢀxO4 is distorted and the Ms value of nanoparticles decreased,
resulting in diminishing r2 values. The MnxFe3ꢀxO4 nanoparticles (x = 0.43) with highꢀperformance
T2 contrast ability provides much higher signal sensitivity for imaging of living subjects compared
with other ironꢀoxideꢀbased CAs.
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EXPERIMENTAL SECTIONS
Materials. 1ꢀoctadecene (tech, 90%) were purchased from Acros Organics. Oleic acid (tech, 90%),
manganese chloride tetrahydrate (99%) were purchased from Alfa Aesar. Iron (III) chloride
anhydrous (>97%), sodium oleate, trisodium citrate dehydrate, hexane, and ethanol were purchased
from Sinopharm Chemical Reagent Co. Ltd. (Shanghai, China). All chemicals were used as received
without further purification.
Characterization. Transmission electron microscopy images (TEM) and highꢀresolution TEM
(HRTEM) were obtained by JEOL JEMꢀ2100 microscope with an accelerating voltage of 200 kV.
The Xꢀray powder diffraction (XRD) patterns of the nanoparticles were acquired on a Rigaku Ultima
IV system (with CuꢀKα radiation, 30mA, 40 kV, scan angle (20°ꢀ70°), Sampling .W = 0.02, DivSlit
(1/2 Deg), Div. HL. Slit = 10 mm). The energyꢀdispersive Xꢀray (EDX) element mapping was
performed on a Tecnai F30 microscope at 300 kV. The Xꢀray absorption spectra were recorded at
beamline BL14W1 of Shanghai Synchrotron Radiation Facility (SSRF, at Shanghai, China). The
hysteresis loops (MꢀH curves at 300 K) were performed by the superconducting quantum
interference device (SQUID). The hydrodynamic diameters of nanoparticles were measured with the
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dynamic light scattering (DLS) measurements (Malvern Zetasizer nano ZS instrument). The metal
concentration of the samples was measured with inductively coupled plasma atomic emission
spectroscopy (ICPꢀAES).
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Synthesis of iron oleate and manganese oleate complex. A metal oleate complex was carried
out by reacting sodium oleate and metal chlorides according to a reported method with minor
modification. In a typical experiment, 0.811 g of iron chloride (5 mmol) and 4.567 g of sodium
oleate (15 mmol) were dissolved in a mixture of 20 mL ethanol, 15 mL distilled water and 30 mL
hexane. The resulting solution was heated to 70 °C and stirred at that temperature for 4 h. After
cooling to room temperature, the upper layer containing iron oleate was washed three times with
distilled water. The resulting red brownish iron oleate complex in a waxy solid form was obtained
after hexane was volatilized naturally in the dish. The manganese oleate complex (pink waxy solid)
was prepared in a similar way except using manganese chloride as precursors and reacting under N2
atmosphere. Then the manganese oleate complex was dissolved in ODE and sealed for further use.
Synthesis of Fe3O4 and MnxFe3-xO4 nanoparticles. A oneꢀpot synthetic route of MnxFe3ꢀxO4
nanoparticles (using x = 0.43 as example) is as follows: 0.903 g (1 mmol) of iron oleate (synthesized
in a typical method) and 0.104 g (0.167 mmol) manganese oleate were dissolved in 15mL of
1ꢀoctadecene, with the addition of 0.186 mL (0.584 mmol) of oleic acid. The solution was first kept
at 120 °C for 30 min in vacuum to remove air and other impurities then refluxed at 320 °C in N2 for
2 h before cooling to room temperature. The products were separated by centrifugation, washed three
times with ethanol, and dispersed in hexane for further use. The preparation of Fe3O4 nanoparticles is
similar to the procedure without the adding of manganese oleate.
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Transfer Fe3O4 and MnxFe3-xO4 nanoparticles into water. Briefly, sodium citrate in water and
the asꢀprepared nanoparticles in hexane were mixed with the adding of acetone to initiate a
ligandꢀexchange process. The MnxFe3ꢀxO4 nanoparticles were gradually transferred to aqueous media
by replacing oleic acid with sodium citrate, due to the fact that the chelation capability of the citrate
to the nanoparticles surface is stronger than that of the original carboxyl groups of oleic acid. The
sodium citrateꢀcoated Fe3O4 nanoparticles were obtained with similar procedures.
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Cytotoxicity Assay. The cytotoxicity of sodium citrateꢀcoated MnxFe3ꢀxO4 nanoparticles (x = 0.09,
0.43 and 1.06) was assessed by 3ꢀ(4,5ꢀdimethylthiazolꢀ2ꢀy1)ꢀ2,5ꢀdiphenyltetrazolium bromide (MTT)
assay using SMMCꢀ7721 cells. Cells were firstly seeded into a 96ꢀwell plate with a density of 1 ×
104 cells/well in RPMI 1640/ DMEM, and incubated under 5% CO2 at 37 °C overnight. The cells
were then incubated with the sodium citrateꢀcoated MnxFe3ꢀxO4 nanoparticles (x = 0.09, 0.43 and
1.06) at different [Mn + Fe] concentrations (0.469, 0.938, 1.875, 3.75, 7.5, 15, 30, 60 and 120 ꢁg/mL)
for 24 h. Then 100 ꢁL of new culture media containing MTT (0.5 ꢁg/mL) was added to each well
and the cells were further incubated at 37 °C for 4 h. The OD492 value (Abs.) of each well was
measured using a MultiSkan FC microplate reader immediately. Cell viability was calculated from
OD492 values.
Cell uptake study. The SMMCꢀ7721 cells (1 × 106) were seeded in dishes for 12 h, washed twice
with PBS and incubated with 10 mL of RPMI 1640 containing MnxFe3ꢀxO4 nanoparticles (x = 0.43)
with different concentrations at 37 °C for 5 h. After harvesting the cells and washing them with PBS
buffer for three times, we transferred the cells into 0.6 mL graduated centrifuge tubes and collected
MR images on a 0.5 T MR scanner. We calculated the SNR by the equation: SNR = SI/SDnoise, where
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SI represents signal intensity and SD represents standard deviation. The SNR changes were
calculated by the equation: SNR = |SNRpost ꢀ SNRpre|/SNRpre.
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Relaxivity and in vitro MRI phantom studies. The samples were firstly scanned using 0.5 T
NMI20ꢀAnalyst NMR system. T1ꢀ and T2ꢀweighted phantom images were acquired by a 2D
multiꢀslice spinꢀecho (MSE) sequence: TR/TE = 200/2 ms (T1), TR/TE = 2000/40 ms (T2), 512 × 512
matrices. The relaxivities and MRI phantom images at 1.5 T were recorded by HTꢀMICNMRꢀ60
system. T1ꢀ and T2ꢀweighted phantom images were acquired by a spinꢀecho (SE) sequence: TR/TE =
100/8.3 ms (T1), TR/TE = 5000/37 ms (T2), 128 × 128 matrices, thickness = 0.8 mm, slice = 1. The
relaxivities and MRI phantom images at 7 T (Varian 7T micro MRI) were recorded using a T2ꢀ
weighted fast spinꢀecho multiꢀslice sequence (fSEMS) (TR/TE = 2500/40 ms, FOV = 80 × 80 mm,
thickness = 2 mm, slice = 1).
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In vivo liver MRI. In vivo MR imaging of liver was performed with BALB/c mice as a model. All
animal experiments were carried out according to the protocol approved by Institutional Animal Care
and Use Committee of Xiamen University. After intravenous injection of Fe3O4, MnxFe3ꢀxO4 (x =
0.43 and x =1.06) and Feraheme at a dose of 1 mg Fe/kg of mouse body weight, we obtained the
coronal and transverse plane MR images using an fSEMS sequence. The parameters are: TR/TE =
2500/32.8 ms, thickness = 1 mm, averages = 4, FOV = 40 × 40 mm (transverse plane) and FOV = 40
× 40 mm (coronal plane) on a Varian 7T micro MRI scanner.
RESULTS AND DISCUSSION
Synthesis and characterization. We used a simple and straightforward method to fabricate
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MnxFe3ꢀxO4 nanoparticles by thermal decomposition of iron oleate and manganese oleate as
precursors and oleic acid as surfactant in 1ꢀoctadecene. We produced MnxFe3ꢀxO4 nanoparticles (x
from 0.09 to 1.06) with different manganese contents by tuning the ratios of two precursors and
prepared Fe3O4 nanoparticles of similar size. Transmission electron microscopy (TEM) images
(Figure 1) show that the asꢀsynthesized MnxFe3ꢀxO4 nanoparticles are of uniform spherical shape and
narrow size distribution (about 18.5 nm in diameter, see Figure S1). We chose MnxFe3ꢀxO4
nanoparticles (x = 0.43) to further characterize their structure. TEM images show they are uniform
and high resolution TEM (HRTEM) images reveal good crystallinity with a lattice spacing distance
of 0.30 nm (Figure 2a), which corresponds to (220) planes of inverse spinel magnetite. Selected area
electron diffraction (SAED) also shows a crystalline nature of magnetite (Figure 2b). As shown in
Xꢀray photoelectron spectroscopy (XPS) spectra (Figure S2), the peaks of 710.6 eV and 724.1 eV are
assigned to Fe 2p3/2 and Fe 2p1/2 of magnetite,32ꢀ33 while the peaks of 641.4 eV (Mn 2p3/2) and 653.1
eV (Mn 2p1/2) indicate the oxidation state of Mn(II).34ꢀ35 The energyꢀdispersive Xꢀray line scanning
analysis (EDX) (Figure 2c) and element mapping (Figure 2d) suggest that Mn(II) ions are
homogeneously distributed in iron oxide nanoparticles.
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Structures and properties. Xꢀray diffraction (XRD) patterns of MnxFe3ꢀxO4 nanoparticles (Figure
3) show the diffraction peaks of inverse spinel structures of magnetite (JCPDS no. 01ꢀ089ꢀ0691).
However, we found that all the peaks had varying degrees of shift compared to those of magnetite.
The peak of (220) gradually shifted from 30.3 (x = 0) to 29.2 (x = 1.06). Similarly, the peak of (300)
shifted from 35.5 to 34.7, (400) shifted from 42.9 to 42.0, (511) shifted from 57.0 to 56.2, and (440)
shifted from 62.5 to 61.4. The shifting distances of the peaks are not the same, indicating that the
shifts are not caused by baseline drift during data collection. It is probably due to the doping of
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Mn(II) ions which partially change the structure of iron oxides. Since the radius of Mn(II) ions (67
pm) is larger than those of Fe(II) ions (61 pm) and Fe(III) ions (55 pm), Mn(II) ions occupying either
octahedral or tetrahedral interstitial sites in the inverse spinel structure of magnetite may cause lattice
distance bigger than that of pure magnetite. According to Bragg’s law nλ = 2dsinθ, since λ is a
constant determined by CuꢀKα radiation and n is the same, θ would diminish as d increases, in other
words, the peaks of MnxFe3ꢀxO4 nanoparticles in XRD patterns should display left shifting. This
phenomenon is further confirmed by the analysis of HRTEM images of MnxFe3ꢀxO4 nanoparticles
with different manganese doping levels (Figure 4). The distances of crystal lattice are increased from
0.29 nm (x = 0, Fe3O4) to 0.30 nm (x = 0.43, MnxFe3ꢀxO4), and finally is 0.31 nm (x = 1.06,
MnxFe3ꢀxO4). To analyze the tiny but significant change, we also measured the lattice distance of
these nanoparticles by counting a large number of HRTEM images to make an average (the method
and the details are showed in Table S1). This result indicates that the lattice distance gradually
increases as manganese doping level is elevated. The calculated spacing from XRD analysis is close
to the lattice distance obtained from HRTEM images, confirming the augment tendency of lattice
distance as manganese doping level increases. It is also noteworthy that when the doping level is less
than 0.43, the peaks in XRD show small shifts compared to those of Fe3O4, while the peaks shift
significantly when the doping level is higher than 0.47. This result indicates that high doping level of
manganese would disturb the original structure of MnxFe3ꢀxO4 greatly. Meanwhile, the lattice fringes
become unclear and disturbed when manganese doping level is higher than 0.47, finally the lattice
fringe is considerably distorted in the case of x = 1.06. All these results indicate that as manganese
doping level increases, the crystal structure change of MnxFe3ꢀxO4 nanoparticles becomes significant,
which is reflected by the increment in lattice distances and the disturbed lattice fringes.
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Magnetic Properties. We measured the magnetic properties of MnxFe3ꢀxO4 nanoparticles at a
magnetic field of 5 T at 300 K. Fieldꢀdependent magnetization (MꢀH) curves (Figure 5a) indicate that
MnxFe3ꢀxO4 nanoparticles show different magnetic properties as manganese doping level changes.
The coercivity in hysteresis loops is negligible at 300 K for all the samples. However, the
MnxFe3ꢀxO4 nanoparticles exhibit typical superparamagnetic behaviors when the manganese doping
level is less than 0.61, while gradually become partially paramagnetic as the doping level increases.
The magnetizations of the three samples (x = 0.79, 0.93, and 1.06) tend to be unsaturated even at the
maximal applied magnetic field of 5 T, indicating that these three samples exhibit partially
paramagnetic behaviors at room temperature. This is probably attributed to the doping manganese
ions which disturb the longꢀrange order of magnetic spins in magnetite and interrupt the magnetic
dipolar coupling. The Ms values (Table S4) of MnxFe3ꢀxO4 nanoparticles are 50.8, 60.1, 67.7, 73.3,
83.9, 89.5, 75.6, 69.9, 60.9, 44.0, 35.2 and 21.1 emu/g (emu/mass of Fe and O atoms in total) for x
from 0 (Fe3O4) to 1.06, respectively. The Ms increases from 50.8 emu/g to 89.5 emu/g as manganese
doping level rises from x = 0 to x = 0.43 (Figure 5b). This is because Mn(II) ions have five single
electrons, which is the same as Fe(III) ions, and one more than Fe(II) ions. With an external
magnetic field, the magnetic spins in Oh sites align parallel and those in Td sites align antiparallel
with the direction of the external magnetic field.13 Therefore, with the assumption that Mn ions
prefer Td sites, the net magnetic spins of MnxFe3ꢀxO4 unit is calculated to be (4+x) ꢁB (for x>1, it is
always 5 ꢁB), higher than that of Fe3O4 unit with 4 ꢁB, which explains that magnetic susceptibility of
MnxFe3ꢀxO4 is enhanced as manganese doping level increases. However, as the doping level further
augments, the Ms shows a stepwise decrease to 21.1 emu/g (x = 1.06), which may be due to the fact
that the crystal structure is disturbed severely by a large amount of manganese doping. According to
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XRD patterns and lattice distances analysis, manganese ferrite nanoparticles undergo lattice
distortion at high manganese doping level, which interrupts the magnetic dipolar coupling and results
in low saturation magnetization.
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Relaxivity Measurements. Coating methods have been well developed in recent years for magnetic
nanoparticles as contrast agents.36ꢀ38 To achieve good biocompatibility, we coated Fe3O4 and
MnxFe3ꢀxO4 nanoparticles with sodium citrate to confer water solubility. We chose sodium citrate but
not macromolecules (for example, PEG and PVP with large volume) because sodium citrate coating
would not change the diameter of nanoparticles significantly. Researches have already showed that
nanoparticles smaller than 50 nm can escape phagocytosis to some extent, resulting in a prolonged
circulation time,39ꢀ41 therefore maintaining the small size of nanoparticles would be beneficial for
biomedical applications. Dynamic light scattering (DLS) analysis (Figure S3 and Table S3) indicates
that Fe3O4 and MnxFe3ꢀxO4 nanoparticles are very stable with narrow size distribution in water.
Moreover, there is little change in the diameter between the asꢀprepared nanoparticles and the
nanoparticles after coating with sodium citrate.
We then studied the contrast enhancement abilities of MnxFe3ꢀxO4 nanoparticles with different
manganese doping levels. We firstly performed the relaxivity test on a 0.5 T MRI scanner. It is
noteworthy that both the T1 and T2 relaxivities showed interesting trends as the manganese doping
level increases. The r2 values (Figure 6a and Table S4) are 128.3 ± 2.9 mMꢀ1sꢀ1 for Fe3O4 (x = 0, with
respect to iron concentration), and 206.9 ± 1.9, 269.3 ± 6.0, 375.9 ± 14.1, 459.5 ± 5.7, 506.6 ± 18.7,
396.7 ± 11.5, 312.1 ± 14.8, 244.4 ± 2.6, 154.4 ± 1.2, 117.3 ± 0.6, 77.7 ± 2.4 mMꢀ1sꢀ1 (with respect to
total metal ion concentration) for MnxFe3ꢀxO4 nanoparticles (from x = 0.09 to x = 1.06), respectively.
The highest r2 value is 506.6 ± 18.7 mMꢀ1sꢀ1 when x = 0.43, 4 times higher than that of Fe3O4 and 6.5
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times higher than that of MnxFe3ꢀxO4 nanoparticles (x = 1.06), which is mainly attributed to the
largest saturation magnetization. According to quantum mechanical outer sphere theory, saturation
magnetization plays an important role in transverse relaxation, and a larger Ms brings about a higher
r2. Therefore, T2 contrast abilities of ferrite nanoparticles should show a similar trend to their
saturation magnetizations, peaking at x =0.43, which is consistent with experimental results (Figure
5b and Figure 6b). We also performed phantom imaging analysis. In T2ꢀweighted MR images, the
tissue with a short T2 relaxation time appears dark. We can observe that with the increase of total
metals concentrations, the signal intensity of T2ꢀweighted phantom images reduces gradually in all
the samples (Figure 6c). The T2 contrast effect is the strongest when manganese doping level is 0.43,
weakened as the doping level is reduced to 0 or increased to 1.06 gradually, indicating that x = 0.43
is the optimal manganese doping level of MnxFe3ꢀxO4 nanoparticles as T2 CAs.
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Meanwhile, we also evaluated T1 contrast abilities of MnxFe3ꢀxO4 nanoparticles at different
manganese doping levels (Figure S4a,b). The r1 values of Fe3O4 (x = 0) and MnxFe3ꢀxO4
nanoparticles (from x = 0.09 to x = 1.06) at 0.5 T are 19.4 ± 0.1, 26.8 ± 0.2, 45.1 ± 0.6, 60.1 ± 0.5,
70.3 ± 0.6, 76.5 ± 1.1, 64.2 ± 0.2, 50.5 ± 0.8, 32.4 ± 0.7, 17.0 ± 0.3, 13.7 ± 0.9 and 9.4 ± 0.2 mMꢀ1sꢀ1,
respectively (Table S5). They have the similar trend to r2 values at 0.5 T. Indeed, superparamagnetic
nanoparticles also can shorten T1 relaxation process. The r1 value increases with the manganese
proportion (x less than 0.43) may be attributed to the increased surface Mn2+ ions of MnxFe3ꢀxO4
nanoparticles. Mn2+ ion has more unpaired electrons and longer electronic relaxation time than Fe2+
ion42ꢀ44 , therefore has higher r1 value according to SBM theory.45ꢀ47 The r1 values reduced with
higher manganese proportion might because that the disordered metal atoms on surface lead to an
ineffective coordinating and chemical exchanging process of protons.48ꢀ49 The phantom imaging
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showed the interesting changes of T1 contrast effects clearly (Figure S5). The value of r2/r1 is crucial
to estimate whether the nanoparticles can serve as a T1 or T2 contrast agent.50ꢀ53 High r2/r1 ratio (> 10)
results in T2ꢀ dominated contrast effect and the low ratio (< 5) leads to T1ꢀ dominated contrast
effect.49, 53ꢀ56 For T1ꢀT2 dualꢀmode contrast agents, the suitable r2/r1 value is about 5ꢀ10.57ꢀ61 The r2/r1
ratios of Fe3O4 (x = 0) and MnxFe3ꢀxO4 nanoparticles (from x = 0.09 to x = 1.06) at 0.5 T are 6.6, 7.7,
6.0, 6.3, 6.5, 6.6, 6.2, 5.6, 7.5, 9.1, 8.6, and 8.3, respectively (see Table S5). The moderate r2/r1
values and high r1 values of MnxFe3ꢀxO4 nanoparticles (from x = 0.19 to x = 0.53) suggest that they
can serve as T1ꢀT2 dualꢀmode contrast agents in MRI with low magnetic fields (e.g., 0.5 T). Our
results are also in agreement with this trend in the T1ꢀ and T2ꢀ weighted phantom imaging (Figure S5
and Figure 6c).
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In theory, signalꢀtoꢀnoise ratio (SNR) is proportional to the square of external magnetic field while
noise is directly proportional to external magnetic field, which means that the sensitivity of MR
imaging can be enhanced by applying high magnetic field.62 Taking this factor into account, we also
conducted T1 and T2 relaxivity tests on a 7.0 T MRI scanner (Figure 7). Consistent with the situation
at 0.5 T, the r2 values are 244.2 ± 12.3, 397.1 ± 18.3, 512.5 ± 21.7, 715.6 ± 17.4, 855.3 ± 3.4, 904.4 ±
11.1, 748.4 ± 7.5, 591.3 ± 6.2, 460.0 ± 5.3, 289.5 ± 1.2, 236.4 ± 12.4, and 139.1 ± 1.7 mMꢀ1 sꢀ1 for
Fe3O4 (x = 0) and MnxFe3ꢀxO4 nanoparticles (from x = 0.09 to 1.06), respectively, peaking at x = 0.43
(Figure 7a and Table S4). The strength of magnetic field is an important parameter for the
relaxivities of magnetic nanoparticles.63 The r2 values of the nanoparticles are greatly increased,
while the r1 values are significantly diminished at a high magnetic field.63ꢀ64 The r1 values (Figure
S4c,d) are 1.46 ± 0.02, 1.21 ± 0.13, 0.90 ± 0.05, 0.73 ± 0.01, 0.56 ± 0.01, 0.50 ± 0.01, 0.76 ± 0.02,
0.87 ± 0.05, 1.19 ± 0.02, 1.73 ± 0.09, 1.90 ± 0.11, and 2.19 ± 0.04 mMꢀ1 sꢀ1 for Fe3O4 (x = 0) and
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MnxFe3ꢀxO4 nanoparticles (from x = 0.09 to 1.06), and the r2/r1 ratios are about 165, 328, 569, 980,
1527, 1809, 985, 680, 387, 167, 124, 64, respectively (Table S5). The ultrahigh r2/r1 values suggest
that MnxFe3ꢀxO4 nanoparticles only serve as T2 contrast agents at high fields. It is noteworthy that
MnxFe3ꢀxO4 nanoparticles (x = 0.43) exhibits the highest negative contrast effect (Figure 7b) with a r2
value of 904.4 mM−1s−1, which is the highest r2 value ever reported to the best of our knowledge, and
is about 9.2 times higher than that of Feraheme (ferumoxytol, iron oxide nanoparticles with a r2
value of 98.4 mM−1s−1 at 7.0 T, see Figure S6), an approved MRI contrast agent in clinical practice.
The ultrahigh transverse relaxivity leads to a strong T2 contrast effect in MR imaging. As shown in
Figure 7c, compared to the signal of water, a significant dark signal for MnxFe3ꢀxO4 (x = 0.43) was
observed even when the concentration of total metal was only 0.05 mMꢀ1, indicating that these
nanoparticles hold great promise for highly sensitive and accurate detection in imaging and diagnosis.
We also performed the longitudinal and transverse relaxivities of MnxFe3ꢀxO4 (x = 0.43)
nanoparticles at clinical field strengths. The r1 and r2 values of MnxFe3ꢀxO4 (x = 0.43) nanoparticles
are 737.2 ± 16.7 and 19.93 ± 0.17 mMꢀ1 sꢀ1 at 1.5 T, respectively, indicating that MnxFe3ꢀxO4 (x =
0.43) nanoparticles can serve as excellent T2 contrast agents at clinical field strengths.
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In vitro and in vivo MRI studies. Before in vivo studies, we first evaluated the cytotoxicity of
sodium citrateꢀcoated MnxFe3ꢀxO4 nanoparticles (x = 0.09, 0.43, and 1.06) using SMMCꢀ7721 cells
as a model by tetrazoliumꢀbased colorimetric (MTT) assays. They showed no appreciable
cytotoxicity even at high concentrations (up to 120 ꢁg [Mn + Fe] mL−1) after 24 hour incubation of
SMMCꢀ7721 cells, suggesting the good biocompatibility of the waterꢀdispersible MnxFe3ꢀxO4
nanoparticles (Figure S8). Moreover, the particle size changed little after incubation with fetal
bovine serum (FBS), suggesting the good stability of these nanoparticles in the presence of serum
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proteins (Figure S9). We also tested the T1ꢀ and T2ꢀ weighted MRI contrast abilities of MnxFe3ꢀxO4
nanoparticles (x = 0.43) in vitro by incubating SMMCꢀ7721 cells with them at different
concentrations (0.2, 0.4, and 0.8 mM [Mn + Fe]) on a 0.5 T MR scanner (Figure S10 and Table S7).
Cells after being incubated with MnxFe3ꢀxO4 nanoparticles at higher concentration showed brighter
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signals in T1 imaging and darker signals in T2 imaging. SNR changes ꢂSNR (ꢂSNR = |SNRpost
−
SNRpre|/SNRpre) for cells (Table S8) incubated with MnxFe3ꢀxO4 nanoparticles at the concentration of
0.8 mM are 60.5 ± 4.31% in T1 images and 76.1 ± 1.7% in T2 images, demonstrating that MnxFe3ꢀxO4
nanoparticles show both T1 and T2 MR contrast enhancement effects in vitro at a low magnetic field
of 0.5T.
To evaluate the contrast abilities of MnxFe3ꢀxO4 nanoparticles in vivo, we chose Fe3O4 (x = 0)
nanoparticles, MnxFe3ꢀxO4 nanoparticles (x = 0.43 and x = 1.06) as the representative samples, and
used Feraheme as control. Nanoparticles are rapidly taken up by mononuclear phagocyte system
(MPS) and easily accumulated in hepatic Kupffer cells in liver,65ꢀ67 so we focused on liver as the
region of interest (ROI). We used healthy BALB/c mice as the model to conduct the animal
experiments and perform T2ꢀ weighted MRI of liver. After intravenous injection of these four
samples at a dose of only 1 mg [Fe]/kg or 1 mg [Mn + Fe]/kg mouse body weight, we observed
significant signal attenuation for four groups at 0.5, 1, 2, and 4 h post injection (p.i.) of transverse
plane (Figure 8a) and coronal plane (Figure S11a) in the liver region. The liver region became dark
at 0.5 h postꢀinjection, reached maximum dark signals at 2 h and showed brighter signals at 4 h than
those at 2 h. The bright signals at 4 h (also can be confirmed in Table S9 and Table S10 SNR
changes) imply that the nanoparticles started to degrade and were excreted from the body. Previous
studies reported the way taken by cells in vivo to process and degrade iron oxide nanoparticles over
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time.68ꢀ70 Moreover, size plays a strong role in biodistribution and blood circulation, the 18 nmꢀsized
particles we used have numerous benefits for in vivo applications.71ꢀ72 Smaller particles (<10 nm)
reach various organs by crossing the tight endothelial junctions and are rapidly excreted through the
glomeruli of the kidneys.73ꢀ74
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Especially for MnxFe3ꢀxO4 (x = 0.43), the liver region showed obvious dark signals only at 0.5 h
and reached maximum dark signals at 2 h postꢀinjection. These results demonstrate that MnxFe3ꢀxO4
nanoparticles have a fast contrastꢀenhanced effect and relative long diagnostic time window for
several hours after intravenous administration, which could provide more useful information for
diagnosis with enhanced accuracy.
To quantitate the different contrast abilities of four samples, we analyzed the SNRpost/SNRpre value
for each animal of transverse plane (Figure 8b) and coronal plane (Figure S11b). The SNR (%) of
Fe3O4, MnxFe3ꢀxO4 (x = 0.43), MnxFe3ꢀxO4 (x =1.06) and Feraheme at 2 h for transverse plane are
71.7 ± 1.9, 19.0 ± 1.3, 85.0 ± 1.9, 91.8 ± 1.9, respectively. The MnxFe3ꢀxO4 nanoparticles (x = 0.43)
exhibited the best enhancement effects and the maximal ꢂSNR was up to 81.0 ± 1.3% for transverse
plane (Table S9, coronal plane see Table S10), ~2.9 times higher than that of Fe3O4, ~5.4 times
higher than that of MnxFe3ꢀxO4 (x = 1.06), and ~9.9 times higher than that of Feraheme. These results
suggest that MnxFe3ꢀxO4 nanoparticles (x = 0.43) with an ultrahigh r2 value hold great promise as an
excellent T2 contrast agent for sensitive imaging and diagnosis. On the other hand, the high contrast
ability of MnxFe3ꢀxO4 nanoparticles (x = 0.43) indicates a low injection dose, which may imply lower
cost, less side effects, and better potential for clinical translation.
CONCLUSIONS
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In summary, we introduced a facile method to produce a series of manganese doping magnetite
nanoparticles by oneꢀpot synthesis. By tuning the manganese doping level and investigating the
changes in crystal structures and magnetic properties, we uncovered the possible role of manganese
ions in altering magnetite structures and contrast abilities. It is demonstrated that saturation
magnetizations (Ms) and T2 relaxivities of MnxFe3ꢀxO4 nanoparticles increase as the manganese
doping level rises, reach the maximum when x = 0.43, and decrease as the manganese doping level
continues to augment. The optimized manganese ferrite nanoparticles with ultrahigh T2 contrast
ability show a great potential in sensitive imaging and diagnosis. This work provides a strategy to
develop highꢀperformance negative contrast agents by tuning metal composition of nanoparticles.
Furthermore, besides morphology, size, and surface structure,8, 33, 49 composition of ironꢀoxideꢀbased
nanoparticles should be also carefully considered for design of newꢀgeneration T2 contrast agents.
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ASSOCIATED CONTENT
Supporting Information
The Figures S1ꢀS11 and Tables S1ꢀS10. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: jhgao@xmu.edu.cn
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Notes
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The authors declare no competing financial interests.
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Acknowledgements
This work was supported by National Natural Science Foundation of China (81370042, 81430041,
21602186, and 21521004), National Key Basic Research Program of China (2013CB933901,
2014CB744502, and 2014CB932004), Fundamental Research Funds for the Central Universities
(20720160074), and Department of Human Resources of Fujian Province.
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Figure 1. TEM images of Fe3O4 (x = 0) and MnxFe3ꢀxO4 nanoparticles with various manganese
doping levels (x = 0.09, 0.19, 0.31, 0.39, 0.43, 0.47, 0.53, 0.61, 0.79, 0.92, and 1.06). The
nanoparticles are spherical shape with narrow size distribution.
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Figure 2. Characterizations of MnxFe3ꢀxO4 nanoparticles (x = 0.43). (a) Transmission electron
microscopy (TEM) image (inset: HRTEM image), (b) selected area electron diffraction (SAED)
patterns, (c) the energyꢀdispersive Xꢀray line scanning analysis (EDX) line profiles (inset:
STEMꢀHAADF image), and (d) EDX mapping images of MnxFe3ꢀxO4 nanoparticles (x = 0.43).
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Figure 3. Xꢀray powder diffraction (XRD) patterns of MnxFe3ꢀxO4 nanoparticles with different
manganese doping levels. It is noteworthy that the red line was the pattern of MnxFe3ꢀxO4 with the
manganese doping level of 0.47, from which the shifting of peaks became significant with the
increase of manganese doping level.
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Figure 4. Crystal lattices of (220) in HRTEM images of Fe3O4 nanoparticles and MnxFe3ꢀxO4
nanoparticles with different manganese doping levels. The (220) lattice distances were increased
from 0.29 nm (x = 0, Fe3O4) to 0.30 nm (x = 0.43, MnxFe3ꢀxO4), and finally is 0.31 nm (x = 1.06,
MnxFe3ꢀxO4). Meanwhile, the disturbed lattice fringes became significant (after x > 0.43) with the
augment of manganese doping level.
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Figure 5. Magnetic properties of MnxFe3ꢀxO4 with different manganese doping levels. (a)
Fieldꢀdependent magnetization curves (M–H) of MnxFe3ꢀxO4 nanoparticles of various manganese
doping levels at 300 K. (b) The comparison of saturated magnetization (Ms) of above mentioned
MnxFe3ꢀxO4 samples.
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