Cation Exchange of Anisotropic-Shaped Magnetite Nanoparticles

May 2, 2016 - Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital Xiamen University, Xiamen ...
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Cation Exchange of Anisotropic-Shaped Magnetite Nanoparticles Generates High-Relaxivity Contrast Agents for Liver Tumor Imaging Zhenghuan Zhao,†,‡ Xiaoqin Chi,§ Lijiao Yang,† Rui Yang,∥ Bin W. Ren,† Xianglong Zhu,† Peng Zhang,∥ and Jinhao Gao*,† †

State 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 Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China ‡ College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China § Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital Xiamen University, Xiamen 361005, China ∥ Department of Chemistry, Dalhousie University, Halifax NS B3H4R2, Canada S Supporting Information *

ABSTRACT: Cation exchange is a powerful means to adjust the properties of nanocrystals through composition change with morphology retention. Herein, we demonstrate that cation exchange can engineer the composition of iron oxide nanocrystals to dramatically improve their contrast ability in magnetic resonance imaging (MRI). We successfully construct manganese and zinc engineered iron oxide nanoparticles with diverse shapes (sphere, cube, and octapod) by facile cation exchange reactions. Extended Xray absorption fine structure (EXAFS) study indicates that Mn2+ and Zn2+ ions are doped into the crystal lattice of ferrite, and more importantly, most of them are distributed in Td sites of ferrite. These engineered shaped-anisotropic iron oxide nanoparticles exhibit both high saturated magnetization and large effective boundary radii, which leads to remarkable transverse relaxivity (r2), for example, 754.2 mM−1 s−1 for zinc engineered octapod iron oxide nanoparticles. These engineered iron oxide nanoparticles, as highperformance T2 contrast agents for in vivo MR imaging, enable sensitive imaging of early hepatic tumors and metastatic hepatic tumors (as small as 0.4 mm), holding great promise for prompt and accurate diagnosis of cancers and metastases.

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INTRODUCTION Magnetic resonance imaging (MRI) is regarded as a powerful imaging tool because it is noninvasive and capable of generating images with high spatial and temporal resolution.1,2 Magnetic nanoparticles, such as superparamagnetic iron oxide (SPIO) nanoparticles, are employed as T2 contrast agents to improve diagnostic sensitivity and accuracy of MRI.3−7 However, conventional SPIO nanoparticles (e.g., Feridex and Resovist) suffer from low transverse relaxivity (r2), which reduces the sensitivity of contrast agents and limits its application in diagnosis.8 Quantum mechanical outer sphere theory indicates that r2 is highly dependent on both saturated magnetization (Ms) and effective radii (r) of magnetic cores9,10 with the following equation (all of the nanoparticle contrast agents were simulated as spheres): 1/T2 = r2 = (256π 2γ 2/405)V *Ms 2r 2/D(1 + L /a)

coating, and V* is the volume fraction. According to eq 1, we can predict that the higher Ms value or larger efficient radius r, the higher r2 value is. Therefore, design of magnetic nanoparticles with high Ms or large effective radii has emerged as a promising approach to develop new agents with improved T2 contrast ability.11−17 Unfortunately, it is difficult to obtain new magnetic nanoparticles with both high Ms and large effective radii due to the lack of synthetic routes to simultaneously control both composition and morphology. Recently, the successful chemical transformation in nanocrystals, especially postsynthetic substitution reactions, allows for engineering the composition and morphology of nanocrystals.18−20 This strategy opens a new avenue for synthesizing novel iron-oxide-based nanocrystals with well-defined size, composition, and morphology that could hardly be accessed through conventional synthetic routes.

(1)

where Ms and r are saturation magnetization and effective radius of magnetic nanostructure, respectively, D is the diffusivity of water molecules, L is the thickness of an impermeable surface © XXXX American Chemical Society

Received: March 29, 2016 Revised: April 28, 2016

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DOI: 10.1021/acs.chemmater.6b01256 Chem. Mater. XXXX, XXX, XXX−XXX

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prepared SPIO, 10 mL of 1-octadecene, 2 mL of oleyalmine, and 1 ml of tri-n-octylphosphine at 180 °C was kept at this temperature for 2 h. When the reaction was completed, the solution was cooled to room temperature and 30 mL of isopropanol was added to precipitate the nanoparticles. The nanoparticles were separated by centrifugation and washed three times with ethanol. The final product was dissolved in hexane for long-term storage at 4 °C. Engineering SPIO with Zn Cations by Cation Exchange. Because different physical properties of Mn and Zn cation especially atomic radius, diffusion ability, and acid softness could significantly influence the efficiency of cation exchange reaction, a slightly modified synthetic protocol was used to perform the Fe2+ to Zn2+ cation exchange reactions. Typically, 600 mg of ZnCl2, 4 mL of oleylamine, 1 mL of tri-noctylphosphine, and 20 mg of as-prepared SPIO were mixed together in 10 mL of 1-octadecene. The resulting solution was degassed under vacuum for 30 min and protected with nitrogen to remove any low volatile impurities and oxygen at room temperature. After that, the reaction solution was heated to 220 °C quickly, and kept at that temperature for 2 h. When the reaction was completed, the solution was cooled to room temperature and 30 mL of isopropanol was added to precipitate the nanoparticles. The nanoparticles were separated by centrifugation and washed 3 times with ethanol. The final product was dissolved in hexane for long-term storage at 4 °C. Extended X-ray Absorption Fine Structure (EXAFS) Analysis. The X-ray absorption spectra were recorded at beamline BL14W1 of Shanghai Synchrotron Radiation Facility (SSRF, at Shanghai, China). Fe, Mn, and Zn K-edge XAFS spectra were recorded in transmission mode at room temperature using a four channel silicon drift detector (SDD). To do the fitting, WinXAS 3.1 was employed to normalize experimental data. WinXAS 3.1 was also employed to perform the Fourier transformation (FT) to R-space. Different k-ranges were selected to do the FT. R-space was fitted with literature data at Fe K-edge, Zn K-edge, and Mn K-edge. During the fitting, no parameters were fixed. Measurement of MR Relaxivities of As-Prepared and Engineered Nanoparticles. To measure the T2 relaxivities, asprepared and engineered SPIO with different magnetic ion concentrations were dispersed in 1% agarose solution. The samples were scanned using a multiecho T2-weighted fast spin echo imaging sequence (TR/TE = 2500/40 ms, thickness = 2 mm, and repetition times = 2) by 7 T MRI scanner. In Vivo Liver MR Imaging. Animal experiments were executed according to the protocol approved by Institutional Animal Care and Use Committee of Xiamen University. In vivo MR imaging of liver was carried out with BALB/c mouse as a model. After intravenous injection of Feraheme, as-prepared spherical SPIO, spherical ZnIO, and octapod ZnIO at a dose of 1 and 0.5 (mg of Fe)/kg of mouse body weight, respectively, coronal and transverse plane MR imaging were performed using an fSEMS sequence (TR/TE = 2000/32 ms, 256 × 256 matrices, slices = 7, thickness = 2 mm, average = 1, and FOV = 60 × 60) on a 7 T MRI scanner. The MR images were sequentially obtained at 0, 0.5, 1, 2, and 4 h postinjection (n = 3/group). Signal-to-noise ratio (SNR) calculated by the equation SNRliver = SIliver/SDnoise was used to evaluate signal enhancement, where SI represents signal intensity and SD represents standard deviation.

Postsynthetic substitution reactions, including galvanic replacement and cation exchange, represent a simple and versatile tool to achieve nanoarchitectures that are not readily accomplishable via traditional synthetic routes.21−24 Cation exchange reactions have been increasingly utilized as a synthetic means for inaccessible nanomaterials with unique composition and morphology. Typically, nanoscale cation exchange reactions exhibit excellent morphology retention, rapid reaction rates, and tunable thermodynamics,25−28 which make it a particularly attractive synthetic method for transforming ionic nanocrystals. In principle, the high efficiency of cation exchange reactions in semiconductor nanocrystals could be extended more broadly to other ionic nanocrystals.29,30 However, precisely controlling the composition of iron oxide nanocrystals using cation exchange still remains a significant challenge. Herein, we demonstrate the feasibility to control the composition of iron-oxide-based nanoparticles with morphology retention by cation exchange and develop a novel strategy to obtain high-performance MRI contrast agents. We have synthesized diverse-shaped (sphere, cube, and octapod) iron oxide nanoparticles and successfully replaced part of iron cations by manganese or zinc cations through cation exchange reactions. These engineered iron oxide nanoparticles possess both high Ms and large effective boundary radii, which endow them with remarkable capacity for T2 contrast enhancement (e.g., zinc engineered octapod iron oxide nanoparticles have an r2 value of 754.2 mM−1 s−1). Moreover, these engineered iron oxide nanoparticles as high-performance T2 contrast agents manifest stunning sensitivity in liver MR imaging, liver tumor detection, and diagnosis of metastatic hepatic tumor, which is promising for cancer management and clinical practice.

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EXPERIMENTAL SECTIONS Materials. FeCl3 (99%), NaCl (AR), hexane, sodium oleate, isopropanol, and ethanol were purchased from Sinopharm Chemical Reagent Co. Ltd. (Shanghai, China). 1-Octadecene (90%), oleic acid (90%), oleyamine (90%), tri-n-octylphosphine (TOP), MnCl2·4H2O, and ZnCl2 were purchased from Alfa Aesar. All reagents were used as received without further purification. Characterizations. Transmission electron microscopy images (TEM) were taken on JEOL JEM-2100 at 200 kV. The Xray diffraction (XRD) patterns were obtained on a Rigaku Ultima IV system. The energy-dispersive X-ray element mapping was performed on a Tecnai F20 microscope at an accelerating voltage of 300 kV. The X-ray absorption spectra were recorded at beamline BL14W1 of Shanghai Synchrotron Radiation Facility (SSRF, at Shanghai, China). The hydrodynamic diameters of nanoparticles were performed on a Malvern Zetasizer nano ZS instrument. M−H curves were obtained by on a Quantum Design MPMS-XL-7 system. The magnetic ions concentrations of nanoparticles were measured with inductively coupled plasma atomic emission spectroscopy (ICP-AES). In vitro MR images measurements were performed on a 7T MRI scanner (Varian 7T micro MRI System). Engineering SPIO with Mn Cations by Cation Exchange. Hot injection was used to carry out the Fe2+ to Mn2+ cation exchange reactions. Typically, 100 mg of MnCl2· 4H2O was dispersed in 6 mL of degassed oleylamine. After being degassed under a vacuum, the mixture was heated to 120 °C for 15 min to dissolve MnCl2·4H2O to form Mn precursor. After cooled room temperature, the mixture containing Mn precursor was injected into a degassed solution containing 20 mg of asB

DOI: 10.1021/acs.chemmater.6b01256 Chem. Mater. XXXX, XXX, XXX−XXX

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Figure 1. Engineered spherical SPIO nanocrystals by cation exchange. TEM images of (a) as-prepared spherical SPIO, (b) spherical MnIO (Mn/Fe 1:12), and (c) spherical ZnIO (Zn/Fe 1:8). EDX mapping images of (d) as-prepared spherical SPIO, (e) spherical MnIO (Mn/Fe 1:12), and (f) spherical ZnIO (Zn/Fe 1:8). XRD patterns of (g) spherical MnIO and (h) spherical ZnIO, confirming the crystal transformation from Fe3O4 to MxFe3−xO4 (M = Mn or Zn). XPS analysis of (i) Fe 2p and Mn 2p of spherical MnIO nanoparticles, (j) Fe 2p and Zn 2p of spherical ZnIO nanoparticles.

Figure 2. Characterization of engineered SPIO nanocrystals. Fourier transforms of k spectra of (a) spherical MnIO and (b) spherical ZnIO. (c) Scheme of cation exchange in magnetite nanocrystals. (d) Smooth M−H curves of as-prepared spherical SPIO, spherical MnIO, and spherical ZnIO measured at 300 K (inset: M−H curves in low magnetic field areas). (e) ZFC/FC curves of as-prepared spherical SPIO, spherical MnIO, and spherical ZnIO.

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RESULTS AND DISCUSSION Cation Exchange Reactions in Magnetite Nanoparticles. To obtain the next-generation SPIO nanoparticles with both high Ms and large effective radii, we first demonstrate the feasibility to control the composition of magnetite nanoparticles

by cation exchange. Transmission electron microscopy (TEM) images of the as-prepared and engineered SPIO indicate that the size and morphology are well preserved during the cation exchange reactions (Figure 1, and Figure S1 in the Supporting Information, SI). We then analyzed the samples by TEMC

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Table 1. Interatomic Distances R, Coordination Numbers CN, and Debye−Waller Factors σ Obtained by Fitting the Experimental EXAFS Spectra of MnIO at the Fe and Mn K-Edgesa Fe K-edge

a

Mn K-edge

scattering shell

CN

R (Å)

σ2 (Å2)

scattering shell

CN

R (Å)

σ2 (Å2)

Fe−O Fe−Fe

5.3(8) 13.0(20)

1.98(1) 3.08(2)

0.012(3) 0.017(2)

Mn−O Mn−Mn

4.3(14) 14.0(50)

2.00(4) 3.37(3)

0.009(6) 0.011(4)

Annotation: 13.0(20) means 13.0 ± 2.0, 5.3(8) means 5.3 ± 0.8, 1.98(1) means 1.98 ± 0.01, 0.012(3) means 0.012 ± 0.003.

Table 2. Interatomic Distances R, Coordination Numbers CN, and Debye−Waller Factors σ Obtained by Fitting the Experimental EXAFS Spectra of ZnIO at the Fe and Zn K-Edges Fe K-edge

Zn K-edge

scattering shell

CN

R (Å)

σ2 (Å2)

scattering shell

CN

R (Å)

σ2 (Å2)

Fe−O Fe−Fe

5.0(7) 11.0(20)

1.98(1) 3.09(2)

0.013(3) 0.017(3)

Zn−O Zn−Zn

3.6(13) 11.0(40)

1.95(3) 3.34(2)

0.010(7) 0.011(4)

alteration of the local environment around the remaining Fe cations after the Mn2+ and Zn2+ ions are introduced.35 The FTEXAFS of engineered SPIO at Fe, Mn, and Zn K-edges all have two major scattering shells located in the similar R range (1−3.5 Å), suggesting that Mn2+ and Zn2+ ions should be doped into the crystal lattice of magnetite. The first peak in the FT EXAFS spectra around 1.6 Å is due to backscattering from the nearest neighboring oxygen anions. The second peaks in the r-space range of 2−4 Å should be caused by the backscattering from the nearest metal atoms.36 Because the amplitudes of these two peaks depend on whether the metal cations occupy octahedral (Oh) or tetrahedral (Td) site, we performed a standard two-shell EXAFS fit consisting of metal−oxygen (Me−O) and metal−metal (Me− Me) shell to extract the quantitative local structural information as well as to determine the actual positions of Mn2+ and Zn2+.37 All the best fits presented in Figure 2 are in good agreement with the experimental EXAFS. The parameters for MnIO and ZnIO extracted from the fitting analysis are given in the Table 1 and Table 2, respectively. In the Fe K-edge EXAFS, the Me−O average coordination number (CN) are 5.3 ± 0.8 and 5.0 ± 0.7 for the MnIO and ZnIO samples, which is between the CN of Fe in Oh (6) and Td (4). These results thus suggest that Fe cations are distributed in both Td and Oh sites in MnIO and ZnIO. In addition, the Mn K-edge CN for the Me−O shell is 4.3 ± 1.4, which is between the CN of Me in Oh (6) and Td (4). However, the CN of Mn for Me−Me shell is 14.0 ± 5.0, which is similar to the theoretical CN of Td sites. These results imply that the Mn cations are located in both Oh and Td sites yet most of them are located in Td sites. Similarly, the Zn K-edge CN of Zn in Me−O (3.6 ± 1.3) is close to the CN of Td sites. Meanwhile, the CN in Me−Me shells (11.0 ± 4.0) is in the range of 6 and 12, corresponding to the CN of Oh and Td sites. These results suggest that most of the Zn cations are located in the Td sites and only a small amount of Zn cations occupy Oh sites. This observation is slightly different from the structure of bulk zinc ferrite where all the Zn cation occupied the Td sites. Such difference could be ascribed to the partial inversion of cation occupancy in nanosized zinc ferrite.34,38 Magnetic Property. We then investigated the magnetic properties of as-prepared and engineered spherical SPIO by a superconducting quantum interference device (SQUID) magnetometer. All samples show smooth M−H curves with no hysteresis at ambient temperature, indicating that all samples exhibit superparamagnetic behaviors (Figure 2d). Importantly, the Ms values of spherical MnIO and spherical ZnIO are significantly higher than that of as-prepared SPIO. The increase

associated energy dispersive X-ray spectroscopy (EDS) and energy-dispersive X-ray element mapping (EDX mapping). The engineered spherical SPIO show high signal at typical peaks of Mn or Zn elements in EDS analysis (Figure S2 in the SI). In agreement with the EDS results, the energy-dispersive X-ray element mapping (EDX mapping) analysis indicate that Mn and Zn signals are significant and homogeneous in the engineered SPIO, while negligible in the as-prepared SPIO (Figure 1d−f). The molar ratios of Mn/Fe in Mn engineered spherical SPIO (spherical MnIO) and Zn/Fe in Zn-engineered spherical SPIO (spherical ZnIO) were determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES) to be about 1/12 and 1/8, respectively. We could also tune Mn/Fe and Zn/ Fe ratios of engineered SPIO by controlling reaction time (Figure S3 in the SI). We then analyzed structure of engineered nanocrystals by X-ray powder diffraction (XRD), X-ray photoelectron spectroscopy (XPS) spectra, and X-ray absorption nearedge structure (XANES). The XRD pattern of engineered SPIO shifted from typical magnetite (Fe3O4, JCPDS no. 01-072-2303) to MxFe3−xO4 (MnFe2O4, JCPDS no. 00-010-0319; ZnFe2O4, JCPDS no. 01-073-1963) (Figure 1g,h and Figure S4 in the SI). The XPS spectra analysis indicate that engineered SPIO reveal a typical magnetite phase with the peaks of iron at 711.4 eV (Fe 2p3/2) and 724.2 eV (Fe 2p1/2). Besides, the Mn 2p3/2 and Zn 2p3/2 peaks of spherical MnIO and ZnIO were measured at binding energy of 640.8 and 1024.2 eV, respectively, which are are similar to previously reported manganese or zinc ferrite nanocrystals (Figure 1i,j).31,32 More importantly, XANES analysis indicates that the edge positions of Mn and Zn cations in MnIO and ZnIO are in good agreement with those of Mn and Zn in typical manganese and zinc ferrite, which strongly reveals that Mn and Zn cations in MnIO and ZnIO are in the oxidation state of +2. (Figure S5 in the SI).33,34 These results confirms the successful crystal transformation from Fe3O4 to MxFe3−xO4 (M = Mn or Zn). Fine Structure. Since magnetic properties of ferrites are closely related to the distribution of cations in spinel metal ferrites, we first analyzed the location structure of as-prepared and the engineered spherical SPIO by extended X-ray absorption fine structure (EXAFS). For all cases, the Fourier transform (FT) amplitude was extracted from EXAFS raw data using the same parameters (e.g., k-weighting, background removal). The Fe Kedges FT-EXAFS of the as-prepared SPIO and the best fits match well (Figure S6 in the SI). Compared to the as-prepared SPIO, the Fe K-edge FT-EXAFS of the engineered SPIO are slightly different (Figure 2a,b). This observation can be ascribed to the D

DOI: 10.1021/acs.chemmater.6b01256 Chem. Mater. XXXX, XXX, XXX−XXX

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Figure 3. Engineering anisotropic-shaped SPIO. TEM images and EDX mapping images of (a) cubic MnIO, (b) cubic ZnIO, (e) octapod MnIO, and (f) octapod ZnIO. Smooth M−H curves of (c) as-prepared cubic SPIO, cubic MnIO, and cubic ZnIO and (g) as-prepared octapod SPIO, octapod MnIO, and octapod ZnIO measured at 300 K using a SQUID magnetometer. ZFC/FC curves of (d) as-prepared cubic SPIO, cubic MnIO, and cubic ZnIO and (h) as-prepared octapod SPIO, octapod MnIO, and octapod ZnIO.

Figure 4. MR contrast enhancement effects of engineered SPIO. T2-weigthed MR images of as-prepared and engineered SPIO with (a) spherical, (b) cubic, and (c) octapod morphologies at various concentrations of total metal ions using a Varian 7 T microMRI scanner. Comparison of Ms and r2 of asprepared and engineered SPIO with (d) spherical, (e) cubic, and (f) octapod morphologies. (g) Comparison of r2 of SPIO, MnIO, and ZnIO with different morphologies and effective radii (n = 3/group).

treatment. The standard zero-field cooling and field cooling (ZFC/FC) measurements show that the blocking temperature (TB) of as-prepared SPIO is 200 K, whereas the TB of spherical MnIO and spherical ZnIO increase to 275 and 290 K, respectively (Figure 2e). Because the changes in TB can be attributed to the strong spin−orbit couplings of Mn2+ or Zn2+,31 these results confirm that the changes of magnetic properties of the engineered SPIO are caused by the successful structure transformation. The improvement of magnetic behaviors

of Ms values with the substitution of Mn and Zn cations could be attributed to the different magnetic spin magnitudes and positions of Fe3+, Fe2+, Mn2+, and Zn2+ cations.13−15 The Ms values of as-prepared SPIO, spherical MnIO, and spherical ZnIO are 49.7, 57.3, and 64.6 emu/g, respectively. In addition, the Ms values of spherical MnIO and spherical ZnIO gradually increase as Mn/Fe and Zn/Fe ratios rise, respectively (Figure S7 in the SI). Note that the samples for measurement were prepared as powder after multistep washing with ethanol and plasma cleaning E

DOI: 10.1021/acs.chemmater.6b01256 Chem. Mater. XXXX, XXX, XXX−XXX

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Figure 5. In vivo liver MR imaging. In vivo MR images of BALB/c mice at 0, 0.5, 1, 2, and 4 h after intravenous injection of (a) Feraheme, (b) as-prepared spherical SPIO, (c) spherical ZnIO, and (d) octapod ZnIO at dose of 1.0 (mg of Fe)/kg in transverse planes. (e) Quantification of relative SNRliver collected at 0, 0.5, 1, 2, and 4 h after intravenous injection of Feraheme, as-prepared spherical SPIO, spherical ZnIO, and octapod ZnIO in BALB/c mice at a dose of 1.0 (mg of Fe)/kg (*p < 0.05 compared to Feraheme group). (f) ICP-MS analysis of liver uptake of Fe after injection of Feraheme, asprepared spherical SPIO, spherical ZnIO, and octapod ZnIO at 4 h (n = 3/group). Note that the contribution from endogenous iron was subtracted.

MR Contrast-Enhanced Ability of Engineered Iron Oxide Nanostructures. These hydrophobic nanoparticles were transferred to aqueous media with excellent colloidal stability (Figure S11−S12, and Table S1 in the SI) via a facile and reliable ligand exchange method.39 The transverse relaxivity (r2) measurements indicate that the engineered SPIO with higher Ms exhibit much stronger T2 contrast effects than the as-prepared SPIO at both 7 and 0.5 T MRI scanners (Figure 4, and Figure S13 in the SI). The r2 values of the as-prepared spherical, cubic, and octapod SPIO are 185.2, 393.7, and 621.2 mM−1 s−1 (metal ions) at 7 T, respectively. As expected, spherical MnIO, cubic MnIO, and octapod MnIO show much higher transverse relaxivity with the values of 385.3, 557.2, and 693.5 mM−1 s−1 (total metal ions), respectively. Remarkably, spherical ZnIO, cubic ZnIO, and octapod ZnIO possess r2 values as high as 473.9, 677.5, and 754.2 mM−1 s−1, respectively (Figure 4e−f). Moreover, the r2 values of cubic and octapod nanocrystals with larger effective radii are remarkably higher than that of spherical nanocrystals (Figure 4g). It is worth noting that the octapod ZnIO shows the highest T2 relaxivity with a value of 754.2 mM−1 s−1, which is ∼7.5 times higher than that of Feraheme (Ferumoxytol, 99.6 mM−1 s−1, Figure S14 in the SI), a clinically approved iron oxide nanoparticle used as an MRI contrast agent in preclinical and clinical studies.40 These results indicated that controlling the morphology and composition of SPIO nanoparticles to develop SPIO with high Ms value and large effective radius is a universal approach to construct high-performance T2 contrast agents. In Vivo Liver MR Imaging. To verify that the engineered SPIO display better contrast effects than traditional and commercial SPIO, we chose octapod ZnIO, spherical ZnIO, as-prepared spherical SPIO (traditional SPIO), and Feraheme (commercial SPIO) as representative samples for in vivo imaging. Before the animal study, we first tested the cytotoxicity of these samples using the SMMC-7721 cell line as a model. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that all samples have no appreciable cytotoxicity for 24 h even at concentration up to 50 μg Fe/mL, suggesting their high biocompatibility (Figure S15 in the SI). After confirming that these engineered SPIO are biocompatible,

demonstrate the feasibility to control the composition of ironoxide-based nanoparticles by cation exchange and permit us to develop high-performance MRI contrast agents with high Ms and large effective radius. Engineering Anisotropic-Shaped SPIO with Mn and Zn Cations by Cation Exchange. The anisotropic-shaped iron oxide nanocrystals, such as cubic and octapod SPIO, possess significant higher effective radii than spherical SPIO. In particular, when the geometric volumes are the same, the effective radii of octapod and cubic SPIO are ∼2.4 and ∼1.4 times as large as those of spherical SPIO, respectively (Figure S8 in the SI).16 We synthesized MnIO and ZnIO with cubic and octapod morphologies using similar protocol. TEM images show that the size and shape are well preserved during cation exchange reactions (Figure 3, and Figure S9−S10 in the SI). The EDX mapping analysis indicates that the Mn or Zn are homogeneously distributed in the engineered SPIO (Figure 3). The ICP-AES analysis further confirms that part of iron ions are replaced by manganese or zinc ions. The molar ratios of Mn/Fe are 1/13 and 1/15 for cubic and octapod MnIO, respectively; and the molar ratios of Zn/Fe are 1/14 and 1/18 for cubic and octapod ZnIO, respectively. The different degrees of cation exchange may be attributed to different morphology of as-prepared SPIO. We then investigated the magnetic property of these as-prepared SPIO and engineered SPIO by a SQUID magnetometer. As expected, the engineered SPIO shows significantly higher Ms values than as-prepared SPIO (Figure 3c,g). The increments of Ms values for cubic MnIO and cubic ZnIO are 9 and 23 emu/g, respectively. Meanwhile, cation exchange results in elevations in Ms for octapod MnIO and octapod ZnIO by 7 and 11 emu/g, respectively. The ZFC/FC curves show that TB values of engineered SPIO are much higher than that of corresponding SPIO (Figure 3d,h). These results strongly suggest that the successful structure transformation with morphology retention significantly improves magnetic properties of original iron oxide, demonstrating that cation exchange is an efficient tool to engineer anisotropic-shaped iron oxide nanocrystals with both high Ms values and large effective radii. F

DOI: 10.1021/acs.chemmater.6b01256 Chem. Mater. XXXX, XXX, XXX−XXX

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Figure 6. Ultrasensitive imaging and diagnosis of in situ hepatic tumors. In vivo MR images of orthotopic xenograft liver tumors at 0, 0.5, 1, 2, and 4 h after intravenous injection of (a) Feraheme, (b) as-prepared spherical SPIO, (c) spherical ZnIO, and (d) octapod ZnIO in sagittal plane. (e) Contrastto-noise ratios (CNRs) of tumor-to-liver contrasts at 0, 0.5, 1, 2, and 4 h after administration of Feraheme, as-prepared spherical SPIO, spherical ZnIO, and octapod ZnIO at a dose of 1.0 (mg of Fe)/kg (*p < 0.05 compared to Feraheme group). (f) ICP-MS analysis of liver and tumor uptake of Fe after injection of Feraheme, as-prepared spherical SPIO, spherical ZnIO, and octapod ZnIO (n = 3/group). Note that the contribution from endogenous iron was subtracted. (g) Prussian blue staining images of liver and tumor tissues after intravenous injection of Feraheme, as-prepared spherical SPIO, spherical ZnIO, and octapod ZnIO for 4 h. Scale bar is 100 μm for all images.

using these contrast agents with high Ms and large effective radii can potentially reduce dosage, cut down the cost, and most importantly, minimize the potential side effects. Accurate Imaging and Diagnosis of In Situ Hepatic Tumors. To further evaluate the ability of engineered nanocrystals for imaging hepatocellular carcinoma, we conducted T2-weighted MRI on BALB/c mice bearing orthotopic H22 tumor model. Because hepatic tumors contain much less active Kupffer cells and macrophages, they do not accumulate nanoparticles as efficiently as normal liver tissues.42 Thus, hepatic tumors would show pseudopositive contrast as compared to normal liver tissues.43 Notably, the injection of engineered SPIO, especially octapod ZnIO, results in much higher MR contrast in tumor sites than that of as-prepared spherical SPIO and Feraheme, leading to easier differentiation between hepatic tumors and normal liver tissues (Figure 6a−d). To quantify the contrast enhancement, we calculated the contrast-to-noise ratio (CNR) values by analyzing the area of images corresponding to liver and tumor (Figure 6e). The calculated CNR values of the engineered SPIO groups are significantly higher than those of asprepared spherical SPIO and Feraheme groups (p < 0.05), indicating the higher detection accuracy and lower detection limit for liver tumor imaging than traditional and commercial SPIOs (Table S3 in the SI). The ICP-MS analysis and Prussian blue staining indicate that the uptake of octapod ZnIO, spherical ZnIO, as-prepared spherical SPIO, and Feraheme in liver are comparable, whereas it is negligible in tumors (Figure 6f,g). These results are highly consistent with the fact that hepatic

we conducted T2-weighted in vivo liver MR imaging using octapod ZnIO, spherical ZnIO, as-prepared spherical SPIO, and Feraheme. We indeed observed noticeable signal attenuation in the liver regions after intravenous injection of as-prepared spherical SPIO, spherical ZnIO, and octapod ZnIO (1.0 (mg of Fe)/kg) at 0.5 h postinjection (p.i.). However, the T2 signal change in liver is negligible after injection of Feraheme (Figure 5a−d), which is likely a result of much lower injection dose than that of its clinical use.41 To quantify the contrast enhancement, we calculated the signal-to-noise ratio (SNR) and SNRpost/ SNRpre by carefully analyzing regions of interest (Figure 5e, and Table S2 in the SI). It appears that the contrasts of liver in the engineered SPIO groups, including octapod ZnIO and spherical ZnIO, are significantly higher than those in as-prepared spherical SPIO and Feraheme groups (p < 0.05). These results demonstrate that the engineered SPIO with higher r2 values are much more sensitive than traditional and commercial SPIOs for in vivo T2 imaging of liver. Inductively coupled plasma mass spectroscopy (ICP-MS) analysis indicate that the liver uptake amounts of iron in all groups are comparable, proving that the much better contrasts are due to the higher r2 of the engineered SPIO (Figure 5f). The histological assessment of the tissues revealed no organ abnormalities or lesions in any of the treated mice, indicating a good biocompatibility in living subjects (Figure S16 in the SI). By reducing the injection dose of engineered SPIO to 0.5 (mg of Fe)/kg, the contrast enhancements in the liver are still evident, especially for octapod ZnIO (Figure S17, and Table S2 in the SI). These results reveal that G

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Figure 7. Ultrasensitive imaging and diagnosis of metastatic hepatic tumors. In vivo MR images of metastatic hepatic carcinomas before and 1 h after intravenous injection of octapod ZnIO at a dose of (a) 1 (mg of Fe)/kg and (b) 0.5 (mg of Fe)/kg in sagittal and coronal planes. White arrows, orthotopic liver tumors; red arrows, metastatic liver tumors. H&E staining images of (c) orthotopic xenograft liver tumor and (d) suspected metastatic liver tumor in low magnification, scale bars, 200 μm. The corresponding H&E staining images of (e) orthotopic xenograft liver tumor and (f) suspected metastatic liver tumor at a higher magnification, scale bars, 50 μm. (g) Prussian blue staining image of the liver with metastatic liver tumor. The boundary between normal liver tissue (left) and metastatic liver tumor (right) was indicated by dashed line, scale bar, 50 μm.

reported SPIO-enhanced MRI to liver tumor.44,45 Because other liver lesions, such as cysts and hemangiomas, may exhibit hyperintensity on SPIO-enhanced T2-weighted images as well,46 we utilized H&E histology to identify the liver lesions. The H&E staining images of lesions (Figure 7c−f) exhibited similar features as the orthotopic xenograft liver tumor, such as large pleomorphic nuclei, delicate vesicular chromatin, and prominent nucleoli.47 Meanwhile, the diameters of lesions are approximately in the range of 0.4−1.8 mm, which is consistent with the sizes of suspected metastases in T2-weighted imaging and much smaller than that of orthotopic xenograft tumor. These results confirm that these lesions are multiple liver metastases (Figure S20 in the SI). Further Prussian blue staining reveals that the octapod ZnIO did not accumulate in the tumor as it did in the normal liver tissues (Figure 7g), leading to the signal difference between metastatic liver tumor and liver parenchyma on the T2weighted images. These results indicate that we could successfully detect liver metastatic tumors with tiny size (as small as 0.4 mm) in the octapod ZnIO-enhanced MR imaging, manifesting it as a promising means for prompt detection and accurate diagnosis of liver metastases, which is of great significance to cancer management.

tumors do not accumulate nanoparticles as much as normal liver tissues42 and support that the significantly improved contrasts are due to the higher r2 values of the engineered SPIO. After halving the dosage, the engineered SPIO also provided sufficient contrast enhancement to distinguish liver tumors from normal liver tissues, especially octapod ZnIO (Figure S18 in the SI). The CNR values of octapod ZnIO group are as high as 124.4 ± 1.1, 133.7 ± 0.6, 127.2 ± 0.9, and 120.4 ± 1.5% at 0.5, 1, 2, and 4 h p.i., respectively, which are significantly higher than those of asprepared spherical SPIO and Feraheme groups with the injection dose of 1 (mg of Fe)/kg (Table S3 in the SI). These results indicate that the engineered SPIO with ultrahigh T2 relaxivity could significantly improve the diagnostic sensitivity of liver tumor in T2 imaging when using a low injection dosage, which should be of great importance for accurate detection with lower cost and less side effects in clinic. Sensitive Imaging and Diagnosis of Metastatic Hepatic Tumors. Metastasis is the most frequent cause of death for patients with liver cancer, its accurate diagnosis is crucial for adequate treatment planning and prognosis. We utilized octapod ZnIO, which shows the highest contrast ability, to detect the metastatic liver tumor. The metastatic liver tumor model was established by injection of H22 cells (1 × 106) into the liver of mice. When the metastases were formed, we intravenously injected octapod ZnIO into the mice with either a 1.0 or 0.5 (mg of Fe)/kg dose and scanned the animals with a 7 T microMRI scanner (Figure 7a,b). Apart from the orthotopic xenograft tumor, we noted that there were at least three suspected metastatic liver tumors with high intensity in T2-weighted images, whereas these tumors were invisible before administration. We found that the sizes of these suspected metastases were in the range of 0.4 to 1.6 mm (Figure S19 in the SI), which was significantly lower than the detection limit of previously

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CONCLUSIONS In conclusion, we report an innovative and universal strategy for transition-metal-ion engineered iron oxide nanocrystals by morphology-controllable synthesis and subsequent cation exchange. The cation exchange is capable of introducing transition metal ions into iron oxide nanocrystals with retention of morphology (e.g., sphere, cube, and octapod), which could be extended to composition engineering of other metal oxide nanoparticles. This process is demonstrated to be a valuable tool for developing novel nanoparticles with tunable magnetic H

DOI: 10.1021/acs.chemmater.6b01256 Chem. Mater. XXXX, XXX, XXX−XXX

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properties, which is of great interest for applications in magnetoelectronics, new materials, energy conversion, and biomedicine. Remarkably, these newly derived iron oxide nanoparticles show exceptional T2 relaxivity, which is ascribed to their increased saturated magnetization and effective radii. Their excellent magnetic properties confer themselves an impressive T2 contrast enhancement effect, making them a promising agent for ultrasensitive MR imaging. Demonstrated by the in vivo imaging experiments, these engineered contrast agents manifest a great potential in detecting early liver tumors and metastatic liver tumors utilizing contrast-enhanced MR imaging. We believe that this universal strategy of generating high-performance T2 contrast agents for MR imaging will open exciting avenues for prompt detection and sensitive diagnosis of cancers and metastases.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemmater.6b01256. Additional experimental details, size distribution histograms, TEM and EDS images, XRD patterns, XANES spectra, Fourier transforms, magnetic properties, comparison of the effective radii, EDX mapping images, DLS analyses, MR relaxivities and images, cytotoxicity analysis, organ histology, measurement of the size of tumors, summary of sizes of nanoparticles, and MR signal-to-noise and contrast-to-noise ratios. (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Author Contributions

(Z.Z. and X.C.) These authors contributed equally to this work. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Key Basic Research Program of China (2013CB933901, 2014CB744502, and 2014CB932004), National Natural Science Foundation of China (21222106, 21521004, 81370042, and 81430041), and Fok Ying Tung Education Foundation (142012).

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