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Precisely tuning the contrast properties of ZnxFe3-xO4 nanoparticles in magnetic resonance imaging by controlling their doping contents and sizes Yuanyuan Ma, Jianbi Xia, Chenyang Yao, Fang Yang, Stefan G. Stanciu, Peng Li, Yinhua Jin, Tianxiang Chen, Jianjun Zheng, Guoping Chen, Hongxin Yang, Liqiang Luo, and Aiguo Wu Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.9b01582 • Publication Date (Web): 14 Aug 2019 Downloaded from pubs.acs.org on August 14, 2019

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Chemistry of Materials

Precisely tuning the contrast properties of ZnxFe3-xO4 nanoparticles in magnetic resonance imaging by controlling their doping contents and sizes Yuanyuan Maa,b, Jianbi Xiac, Chenyang Yaoa,b, Fang Yanga,*, Stefan Stanciud, Peng Lia, Yinhua Jinc, Tianxiang Chena,*, Jianjun Zhengc, Guoping Chenc, Hongxin Yanga, Liqiang Luob,*, Aiguo Wua,* a

Cixi Institute of Biomedical Engineering, CAS Key Laboratory of Magnetic Materials and

Devices, & Key Laboratory of Additive Manufacturing Materials of Zhejiang Province, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, P.R. China bDepartment

of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai,

P.R. China. cHwaMei dCenter

Hospital, University of Chinese Academy of Sciences

for Microscopy-Microanalysis and Information Processing, University Politehnica of

Bucharest, Bucharest, Romania.

*corresponding author

ABSTRACT: Given that the contrast of Zn doped Fe3O4 nanoparticles (ZnxFe3-xO4) in magnetic resonance imaging (MRI) depends on their intrinsic chemical and physical properties such as doping content or size, being able to finely control these characteristics is very important, but at the same time very challenging. In this work, we introduce a novel doping mechanism and present how various desired MRI contrast levels can be precisely achieved by synthesizing in a controlled and reproducible manner ZnxFe3-xO4 nanoparticles exhibiting different Zn doping concentrations

(ZnxFe3-xO4,

x=0/0.1/0.2/0.3/0.4)

and

different

dimensions

(4 nm/7 nm/10 nm). The experimental results show that ZnxFe3-xO4 NPs of a specific 1 ACS Paragon Plus Environment

Chemistry of Materials 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

dimension form a system whose saturation magnetization and crystal structure can be easily tuned by adjusting its Zn doping content. The proposed model enables thus the exact tuning of MRI contrast by controlling NP doping content and size. The utility of our study is not restricted to the case of the considered material, as it can be easily extrapolated and applied in the case of other divalent transition metal ions doped magnetic NPs, in order to optimize their MRI contrast and eventually other relevant properties for further biomedical application. INTRODUCTION Over the past years magnetic nanoparticles (MNPs) have attracted very high interest as a result of their immense potential in applications belonging to many fields of science.1-3 Robust, reproducible and finely tunable magnetic properties are crucial for the successful use of MNPs in trending areas of nanomedicine such as drug and gene delivery, therapeutics, diagnostics or imaging.4-7 Therefore, the development of novel MNPs with improved magnetic characteristics and also of novel methods that can optimize existing MNPs are particularly important at this time for overcoming critical bottlenecks in the above-mentioned topics.5, 8-9 In this context, strategies that combine transition metal dopant substitution and ferrite MNPs are currently considered valuable approaches to achieve tunable nanomagnetism. For example, adjustable nanomagnetic properties can be achieved for ferrite based on the facts that: (i) the doping of zinc ions holds a direct impact over the saturation magnetization of this material, and (ii) the doping of cobalt ions can enhance its anisotropy.10-13 The change of doping concentration x stands thus behind the adjustable magnetic properties of various transition metal doped ferrites (e.g., MxFe3−xO4: M = Mn, Co, Ni, Zn, etc.).9, 14 If we take a thorough look at the crystal structure of these materials, we can understand that the substitution position of other metal cations in the ferrite structure is modified in this process, hence resulting in a change of its magnetic properties.15 This mechanism can thus be exploited to accurately design models that can be used to tune the saturation magnetization and other relevant properties. Such utility is extremely valuable in the context of Magnetic Resonance Imaging (MRI), 2 ACS Paragon Plus Environment

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where the saturation magnetization of a contrast agent is an important factor with respect to the achievable contrast effect.11,

16

In this paper we discuss in detail

zinc-doped ferrite MNPs with respect to the above discussed problem. Stoichiometric magnetite (Fe3O4) is an inverse spinel with the cations Fe2+[Oh]: Fe3+[Oh]: Fe3+[Td] = 1:1:1, where [Oh] and [Td] represent octahedral and tetrahedral sites, respectively.12 Its crystal structure diagram of occupying distribution is depicted in Figure 1. In ZnxFe3-xO4, Zn2+ doping substitutes Fe2+/Fe3+ in the crystal structure of Fe3O4, hence, the stable phase of ZnxFe3-xO4 exhibits as well a normal spinel structure, for example Ni2+ and Co2+ can substitute for Fe2+[Oh], and Zn2+ has a strong affinity for Fe3+[Td].15,

17

The magnetic properties of ZnxFe3-xO4 vary with x, depending

significantly on the synthesis and/or postprocessing methods. ZnxFe3-xO4 is usually assumed to be in a complete normal spinel structure with zinc ions exclusively occupying the tetrahedral sites (i.e. all the Fe ions occupy the Oh sites and are trivalent).13 Although several reports have suggested that a small number of Zn2+ would occupy Oh sites when ZnxFe3-xO4 is prepared by coprecipitation,18 ball-milling,19-20

twin-roller

quenching

methods,21

sputtering,22

and

pulsed

laser-deposition,23 the zinc atoms dominantly occupy the Td sites, inducing thus,

the

metastable phase of ZnxFe3-xO4 with the arrangement of Zn2+ and Fe3+ ions being disordered.17 In summary, the position of the zinc ion doping mechanism of ZnxFe3-xO4 may depends on the underlying mechanisms of different synthesis methods, and for this reasons we place a special focus of attention on studying in detail the doping mechanism of our own synthesis system. In the frame of our studies over the doping-mechanism of ZnxFe3-xO4, we regard the optimal doping concentration x as an important index for MRI contrast. By optimal doping concentration we refer to the situation when the MNPs reach the maximum saturation magnetization, hence the value of x can vary. For example, J. Cheon et al. synthesized a series of zinc-doped ferrites by high-temperature pyrolysis and proved by experiment and theory that x = 0.4 was the optimum doping ratio of this system, and they discussed the relationship between magnetic properties of 3 ACS Paragon Plus Environment


contrast media and r2 value in T2 imaging.11 In a different experiment, J M. Byrne et al. reported the biosynthesis of zinc-substituted magnetite nanoparticle with enhanced magnetic properties, and in the case of their experiment the optimum doping concentration was found to be x=0.2, and they tested the r2 values of the proposed nanomaterials.12 Further on, M. Wen et al. synthesized a series of ZnxFe3-xO4 samples by the chemical coprecipitation technique and indicated that the saturation magnetization is maximum when x is 1/3.13 These previous experiments demonstrate that the best doping concentration is indeed different for various synthetic systems. In our experiment, a series of ZnxFe3−xO4 samples (x=0/0.1/0.2/0.3/0.4/0.5) were prepared by an oleic acid/alcohol/water system.14 The reasons behind choosing this synthesis method are due to its potential to provide uniform morphology, controllable particle size and good crystallizability.24-26 Such enhanced tunability which is offered in terms of nanoparticle size or morphology enables us to lay a foundation for our further study over the influence of a single factor of ZnxFe3-xO4 on MRI, and also ensures the reliability of the conclusions that can be drawn.27-28 Compared with other synthesis methods, this approach yields good crystallinity, which is very important as it can be placed in correspondence with high saturation magnetization of the fabricated MNPs. In these circumstances, this method can be used as an ideal mechanism validation model, because the actual doping mechanism is consistent with the results obtained by the perfect crystal model. That is to say, we can strictly control the two variables of size and doping concentration. With our study, we shed light over the doping mechanism of this synthesis system via a series of experimental characterization assays, which are backed up by theoretical calculations and rigorous validation procedures. To this end, we control important properties of the synthesized NPs, e.g. their morphology, to be consistent, and investigate the influence of particle size and doping concentration on T1- and T2-weighted imaging respectively. In terms of applications of the addressed material, our work is focused on studying the effect of ZnxFe3-xO4 as a contrast agent in MRI. EXPERIMENTAL SECTION 4 ACS Paragon Plus Environment

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Chemicals and Reagents. Fe(NH4)2·(SO4)2·6H2O, ZnSO4·7H2O, chloroform (AR) and ethanol (AR) (from Sinopharm Chemical Reagent Co., Ltd.); NaOH (AR, 99%) , oleic acid (OA, AR, 90%), (from Aladdin). All the reagents used in this work are of grade without further purification. Milli-Q water (18.2 MΩ*cm) was used in all experiments. Synthesis of ZnxFe3-xO4 (x = 0/0.1/0.2/0.3/0.4/0.5) nanoparticles. Briefly, 1 g NaOH was dissolved in a mixed solution of 10 ml oleic acid and 10 ml ethanol and stirred until NaOH was dispersed evenly; this solution was coined solution A. Further on, a certain amount of Fe(NH4)2·(SO4)2·6H2O and ZnSO4·7H2O were dissolved in 20 mL Milli Q water, resulting in a precursor solution of particular molar concentration of Fe2+ and Zn2+. This solution was coined solution B. In a further step, solution B was added to the solution A, and the two were stirred until the mixture became brown due to the oxidation of Fe3+. At this point, the solution was transferred to a 50 ml autoclave and heated at 230 ˚C for a specific amount of time; the reaction parameters are presented in Table 1. After the reaction was completed, the autoclave was cooled to room temperature, and the product was deposited on the bottom of the container. At this point, cyclohexane was added to dissolve the bottom product, then excess ethanol was added several times in a centrifugal cleaning procedure in order to achieve a high purity of the product. Finally, the pure NPs were safely stored in cyclohexane or chloroform. Characterization. Transmission electron microscopy (TEM) micrographs were obtained using a JEOL-2100 (JEOL Ltd., Japan) system operating at 200 kV, and analyses over the high-resolution TEM images were performed on a Tecnai F20 (FEI Company, USA) system with selected area electron diffraction (SAED). The nanomaterials imaged by TEM were prepared by dissolving them in cyclohexane, adding 10 μl of the so prepared solution to a Carbon Film (copper 300 mesh), which was further on dried at 300 K. Inductively coupled plasma optical emission spectrometry (ICP-OES) was performed with an Optima 2100 (Perkin Elmer, USA) system. X-ray diffraction (XRD) patterns of the studied samples were collected with a 5 ACS Paragon Plus Environment


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Bruker AXS D8 X-ray diffractometer (Bruker, US) equipped with a Cu-Kα radiation unit, operating at 300K, 40 kV and 40 mA. The nanomaterials investigated by XRD took the form of dried powder (at least 20 mg per specimen). The VSM datasets were collected with a Quantum Design Model-9 (Quantum Design Inc., USA) physical property measurement system (PPMS) at 300 K. The samples characterized by VSM took the form of dry powder (3~8 mg per specimen). The MR imaging and the relaxivity performance of the synthesized NPs were tested using a Philips Avanto MRI (Philips, Netherlands) scanner system with a magnetic field of 1.5 T at 300 K on the premises of Hwa Mei Hospital, University of Chinese Academy of Sciences. The elements and the valence state of the materials were characterized by an AXIS ULTRA DLD (Shimadzu, Japan) system for X-ray photoelectron spectroscopy (XPS) equipped with a monochromatic Cu (Kα) X-ray source. The specimens took the form of dried powder for this measurement. The samples were also characterized at room temperature (300 K) with a Germany Wissel (Wissel, Germany) acceleration drive. Finally, a Mössbauer spectrometer (Wissel, Germany) with a

57Co(Pd)

radiation

source was further used to characterize the samples at 300 K. For this part of the experiment the collected spectra were fitted by the least squares method via Wissoft software and the characterized samples took the form of dry powder (at least 50 mg per specimen). In vitro T1-Weighted MR imaging. Briefly, the ZnxFe3-xO4 (x=0/0.1/0.2/0.3/0.4) were dissolved in cyclohexane at different concentrations. The T1 was acquired using the mixed sequence and T1-weighted imaging was performed with fast acquisition interleaved spin echo (TR = 500 ms; TE = 6.47 ms) at 1.5 T on the premises of HwaMei Hospital, University of Chinese Academy of Sciences. In vitro T2-Weighted MR imaging. Briefly, the ZnxFe3-xO4 (x=0/0.1/0.2/0.3/0.4) were dissolved in cyclohexane at different concentrations. The T2 was acquired using the mixed sequence and T2-weighted imaging was performed with fast acquisition interleaved spin echo (TR = 2000 ms; TE = 13 ms) at 1.5 T on the premises of HwaMei Hospital, University of Chinese Academy of Sciences. 6 ACS Paragon Plus Environment

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RESULTS AND DISCUSSION In Figure 1a to 1d we display the TEM images of the ZnxFe3-xO4 NPs with sizes of approx. 7 nm and x = 0.1/0.2/0.3/0.4, respectively. The particle size distribution map calculated based on the TEM images is shown in Supporting Information (Figure S1). In Figure 1 e) to g) we demonstrate the TEM images of Zn0.2Fe2.8O4 NPs with sizes of 4 nm, 7 nm and 10 nm respectively. The particle size distribution maps are shown in Figure S2 of Supporting Information. We find important to highlight the fact that as the doping concentration continues to increase to x=0.5, the particle size distribution becomes inhomogeneous (Figure S3b). Due to this reason, in order to obtain reliable results for our theoretical simulation and for the next step of MRI control variable test, we choose to use doping concentrations in the range of 0 to 0.4. The Zn2+ doping level (x) was estimated by using ICP-OES. In Figure 1h we depict a high-resolution TEM image of 7 nm Zn0.2Fe2.8O4 nanoparticle, and the inset depicting a SAED mode image (Figure S4), shows different diffraction rings of the synthetic NPs, which demonstrate their crystallinity. In Figure 2a, we illustrate the X-ray diffraction patterns for ZnxFe3-xO4 (x = 0/0.1/0.2/0.3/0.4) under 2θ values ranging from 20˚ to 80˚. We can observe here that the occurring peaks are contributed from the indexed crystal planes, (220), (311), (400), (422), (511), and (440), respectively, and the diffraction peaks of ZnxFe3-xO4 (x = 0.1/0.2/0.3/0.4) are similar to those of pure Fe3O4, indicating that all these samples have a crystal unit with face-centered cubic inverse-spinel structures.10, 29-31 In order to check the peak displacement by changing x, as shown in Figure 3b, the strongest diffraction peak is selected from the (311) plane in the 2θ ranging from 34˚ to 37˚ to study the structure change of the crystal unit. Taking the (311) peak of Fe3O4 as the baseline, we can notice that with the increase of x, the (311) peak tends to shift to lower angle. This takes place because zinc ions with larger atomic radius replace iron ions (bivalent or trivalent) in the Fe3O4 lattice, resulting in the expansion of the crystal unit with a face-centered cubic anti-spinel structure (the increasing of crystal spacing d).10, 32 With the increase of Zn2+ doping concentration, that is, the increase of x from 7 ACS Paragon Plus Environment


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0 to 0.4, the lattice structure is also expanding. In Figure 3a-e we display the Mössbauer spectras of 7 nm ZnxFe3-xO4 NPs with x = 0/ 0.1/0.2/0.3/0.4, respectively. In these spectra it is obvious that resolving hyperfine field (Bhf) splitting into two sets of six lines (spectrum 2 and spectrum 3) is due to the Td site of the ferric ions (Green lines, Bhf ≈ 480 KOe) and the Oh environment of the ferric and ferrous iron ions (Blue lines, Bhf ≈ 450 KOe).

12, 33-34

The two sets of six

lines and their locations indicate that the five samples are Fe3O4 crystals, not α-Fe2O3 (See table 2). The red line (spectrum 1) is due to superparamagnetism. In addition, it can be observed that the positions of the Bhf are modified in the normal range of fluctuations. The five investigated samples (7 nm ZnxFe3-xO4 NPs, x = 0/ 0.1/0.2/0.3/0.4) are small also with small grain size, which results in two sets of six line peaks of not very strong intensity. The Fe3O4 sample has two standard six line peaks of Fe3O4. Compared with Fe3O4, the Bhf of ZnxFe3-xO4 NPs (x = 0.1/0.2/0.3/0.4) decreases due to the change of crystal structure, which takes place as a result of incorporation of Zn2+. Comparing the four samples, we can observe that the two sets of six-line peaks of Zn0.2Fe2.8O4 sample are sharper, and the value of Bhf is close to that of Fe3O4, which shows that the Zn0.2Fe2.8O4 sample has the best crystallinity, followed by the Zn0.1Fe2.9O4 sample; the crystallinities of Zn0.3Fe2.7O4 and Zn0.4Fe2.6O4 gradually become worse. Even at Zn0.4Fe2.6O4, the hyperfine field pattern collapses, which might occur because the phase of zinc ferrite (ZnFe2O4) has been produced due to the excessive amount of Zn2+. The Mössbauer spectras of 4 nm and 10 nm ZnxFe3-xO4 NPs with x = 0.2 are presented in Figure S5 of Supporting Information. In table 2, the isomer shift (IS) represents the relative proportions of Fe3+ and Fe2+. In general, IS < 0.5 corresponds to Fe3+, and IS > 0.5 corresponds to Fe2+. The quadrupole splitting (QS) value is normal, and the Γ/2 is of half-linear width (the smaller this value, the sharpened the peak, hence better crystallinity). These information suggest that the 7 nm Zn0.1Fe2.9O4 and Zn0.2Fe2.8O4 have better crystallinity in zinc doped samples. Combining all the information available in the 8 ACS Paragon Plus Environment

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Mössbauer spectroscopy assays, we can conclude that the addition of zinc leads to a decrease of crystallinity, and hence the Zn0.2Fe2.8O4 specimen has the best crystallinity, followed by Zn0.1Fe2.9O4 sample. The Comparison of the extracted Mössbauer parameters from the Mössbauer spectra of the 4 nm, 7 nm and 10 nm of Zn0.2Fe2.8O4 are present in Table S1 of Supporting Information. Area in the Table means the proportion of superparamagnetic phase and its values of 4 nm, 7 nm and 10 nm Zn0.2Fe2.8O4 are 1, 0.75 and 0.48, respectively. In consequence it shows that the superparamagnetic phase decreases with the increase of particle size. When the particle size is 4 nanometers, the result exhibits complete superparamagnetism. Therefore, superparamagnetism is directly related to particle size. The magnetism of the 7 nm ZnxFe3-xO4 (x = 0/0.1/0.2/0.3/0.4) NPs was measured at 300 K (Figure 4a). The obtained results show that all the samples display superparamagnetic properties; the Ms value of Fe3O4 NPs is about 56 emu/g, which is lower than the value obtained for the 7 nm Zn0.1Fe2.9O4 (62.5 emu/g) NPs and 7 nm Zn0.2Fe2.8O4 (66.8 emu/g) NPs, and is higher than the value obtained for the Zn0.3Fe2.7O4 (48.4 emu/g) and 7 nm Zn0.4Fe2.6O4 (44.9 emu/g) NPs. The Zn0.2Fe2.8O4 NPs exhibit the highest Ms value. In order to observe more clearly the law by which the Ms value changes, we show in Figure 4b the curves of M/M(0) which are normalized by Ms for Fe3O4. The curves reveal that compared with Fe3O4 NPs , in the case Ms increases in the range of x = 0 to x = 0.2, but when x is greater than 0.2, the Ms value gradually decreases. This phenomenon directly reflects the doping mechanism of Zn2+. Figure 4c shows the hysteresis curves of Zn0.2Fe2.8O4 with different particle sizes (4 nm/7 nm/10 nm) and reveals that the gradual increase of the Ms value can be placed in association with an increase in the particle size. Figure 4d depicts an image of the Zn0.2Fe2.8O4 (7 nm) dispersed in ethanol before and after exposure to magnetic field (30 s) which means the NPs has excellent magnetic response. According to the law of saturation magnetization based on the VSM tests, we can establish the mechanism of zinc doping in this synthesis system.10-11, 13 As shown in 9 ACS Paragon Plus Environment


Scheme 1: when x = 0, a partial removal of antiferromagnetic coupling interactions between Fe3+ irons takes place in the Td and Oh sites; when x ≤ 0.2, the nonmagnetic Zn2+ ions tend to occupy the Td site, substituting some of Fe3+ ions, and in order to keep the charge balanced, some Fe2+Oh ions will change into Fe3+Oh, keeping thus the oxygen’s stoichiometry 4.12-13 Because the magnetic moment of Fe3+ ions is larger compared to that of Fe2+ ions (the number of lone pair electrons of Fe3+ ion is 5, and the number of lone pair electrons of Fe2+ ion is 4), the total magnetic moment increases; when x ≥ 0.2, a part of Zn2+ ions will replace the position of Fe3+Td, but some of them tend to occupy Fe2+Oh ions at higher Zn2+ doping concentration, hence the total magnetic moment will be decreased. This means that most of the Zn2+ ions substitute the Fe2+Oh site and a small number of these occupy the Fe3+Td site when the content of Zn2+ ions increases up to a critical amount. In Figure 4a we demonstrate the XPS Fe 2p spectra in order to document the crystal structure of the Fe3O4 NPs. From right to left, the peak fitting analyses are: (i) Fe 2p3/2 can be divided into three peaks according to the valence state (Fe2+ and Fe3+) and the atomic occupation (Oh-site and Td-site), followed by Fe2+Oh (709.795 eV), Fe3+Oh (710.705 eV) and Fe3+Td (712.386 eV); on the left side of the Fe 2p3/2 lies its shake-up peak. The curve can also be divided into 3 shake-up peaks (From right to left, the peak positions are: 714.295 eV, 718.205 eV and 720.205 eV) corresponding to the order of peak fittings of Fe 2p3/2 peaks; (ii) Similar to Fe 2p3/2, the Fe 2p1/2 can be divided as well into three peaks according to the valence state and atomic occupation configuration, followed by Fe2+Oh (723.395 eV), Fe3+Oh (724.305 eV) and Fe3+Td (725.986 eV); on the left side of the Fe 2p1/2 lies its shake-up peak.35-36 The curve can also be divided into 3 shake-up peaks (From right to left, the peak positions are: 728.795 eV, 731.805 eV and 733.805 eV) corresponding to the order of peak fittings of Fe 2p1/2 peaks. Figure 4b shows the XPS Fe 2p spectra and the peak fitting analysis of ZnxFe3−xO4 NPs (x = 0/0.1/0.2/0.3/0.4). Herein we can observe deconvoluting the broad spectra of Fe 2p peaks of the samples into Fe2+Oh, Fe3+Oh and Fe3+Td same as in the case of Fe3O4 with their peak positions in accord with those 10 ACS Paragon Plus Environment

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of Fe3O4.35-38 This situation takes place because these samples exhibit an inverse spinel structure same as the pure Fe3O4. In addition, the XPS results obtained for different samples of Zn 2p are shown in Figure S6 of Supporting Information. Herein the binding energies of Fe3+Oh with larger coordination numbers are slightly higher than Fe2+ Oh, because they have almost the same crystal structure.13 In order to provide a more clear view of the subtle changes in the peak positions, the values of the Fe peaks and Zn peak energies of ZnxFe3−xO4 NPs (x = 0/0.1/0.2/0.3/0.4) are listed in Table 3. It is obvious that the peak positions of Fe 2p peaks, including Fe 2p1/2 position and Fe 2p3/2 position, slightly shift to a higher binding energy side as the amount of Zn doped into Fe3O4 increases. Because the Zn2+ concentration difference that exists between the considered samples is relatively small, the modification in the position of the peaks is also relatively small, but when compared with Fe3O4 (Fe 2p3/2 position: 710.755 eV; Fe 2p1/2 position: 724.247 eV) and Zn0.4Fe2.7O4 (Fe 2p3/2 position: 711.250 eV; Fe 2p1/2 position: 724.915 eV), the peak position shift is more obvious. That is because the proportion of Fe3+Oh ions increases with x, and the Fe3+ has a higher binding energy compared to Fe2+. In addition, the change of Zn 2p positions is closer to the instrument error than that of Fe 2p positions, indicating that there is no change in the positions of Zn peaks between samples.39 It is well known that when magnetic iron oxide is used as a MRI contrast agent, the imaging properties depend on various properties such as particle size, saturation magnetization and the effect of outer complexes.40-43 Because of the effect of particle size, generally speaking, NPs of less than 4 nm tend to be used as T1-weighted contrast agents, while NPs of more than 10 nm tend to be used as T2-weighted contrast agent.44-45 Because of this we choose to use a particle size in the range of 4-10 nm (namely, 7 nm) in order to reduce the impact of particle size, and to be able to focus on the impact of ligand modification in the material over the MRI contrast effect. In a next step of our experiment, we pursued the strict control of one variable in order to observe the influence of the other variable, which is important for ensuring 11 ACS Paragon Plus Environment


that the results are reliable. In this regard, the specific test plans were as follows: (i) Under the same conditions in terms of magnetic field (1.5 T), test sequence, temperature (300 K), contrast agent shape (sphere) and so on, we detect T1-weighted and T2-weighted imaging and relaxation of 7 nm nanoparticles with different saturation magnetization (achieved by controlling the doping concentration of Zn2+), namely ZnxFe3−xO4 NPs with x = 0.1/0.2/0.3/0.4 (ii) Under the same optimum concentration of Zn2+ doping (Zn0.2Fe2.8O4), the changes of T1-weighted and T2-weighted imaging and relaxation were observed by changing the particle size (4 nm/7 nm/10 nm). The performed experiments suggest that the main factors affecting the MRI contrast of materials functionalized in this purpose, such as those investigated in our work, can be divided in two categories: a) the properties of the material itself (particle size, shape, saturation magnetization, etc.), and b) the properties of the outer ligand (water coordination number, etc.).46-47 In this regard, we performed a series of MR imaging and relaxation experiments directly in the cyclohexane phase, which allowed us to obtain a more reliable variation of the contrast effect of the material itself. Further on, we have evaluated the transverse and longitudinal relaxations of NPs exhibiting the same size but various Zn2+ doping content as well as NPs exhibiting the same Zn2+ doping content but different sizes, so that the optimal NP as MRI contrast agents can be performed. Considering that different zinc doping concentrations indirectly represents changes of the Ms values, the laws of the r1, r2 values and of the involved variables (size and Ms value) were obtained for the investigated class of materials. In Figure 7a we illustrate the transverse relaxivities of the 7 nm ZnxFe3−xO4 NPs (x = 0/0.1/0.2/0.3/0.4), while in Figure 7b we depict the corresponding r2 values for 7 nm ZnxFe3−xO4 NPs (x = 0/0.1/0.2/0.3/0.4). It can be observed from these graphs that the ranking of r2 values is as follows: r2 (Zn0.4) < r2 (Zn0.3) < r2 (Zn0) < r2 (Zn0.1) < r2 (Zn0.2), which is consistent with the ranking of Ms values. Moreover, from the T2-weighted imaging (Figure S7a) of the investigated samples, the same rule can 12 ACS Paragon Plus Environment

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be observed as well. When Zn2+ doping concentration stays constant, the same phenomenon that can be observed in Figure 6c-d and Figure S7c occurs, a phenomenon that is dependent on the size of the Zn0.2Fe2.8O4 NPs. Following the implementation of these methods based on the accurate control of the considered variables, we can conclude that: i) the main factor affecting the T2-weighted imaging is the Ms value. The higher the Ms value and the higher the r2 value, the better the collected T2-weighted imaging is. This conclusion does not conflict with previous literature which suggests that iron oxide nanoparticles larger than 10 nm tend to be T2-weighted imaging contrast agents, since the Ms value increases along with the particle size. In the adopted synthesis system, Zn0.2Fe2.8O4 NPs have higher Ms value, so the Zn0.2Fe2.8O4 NPs with ~7 nm also have a very good T2-weighted imaging effect. Furthermore, because this synthesis system yields good crystallinity of this synthesis system and because of the zinc doping, even 4 nm particles exhibit a high r2 value. In medical MRI applications, T1-weighted imaging contrast agents are preferred. This is also because the factors that influence T1-weighted imaging are more complex and the functioning rules are more difficult to obtain compared with T2-weighted imaging. Figure 7a shows the longitudinal relaxivities of Zn0.2Fe2.8O4 NPs with different sizes (4 nm/7 nm/10 nm), and Figure 7b depicts the corresponding r1 values for these samples. It can be observed from these graphs that Zn0.2Fe2.8O4 has the highest r1 value under the same particle size. According to Figures 7c-d, we can see that 7 nm Zn0.2Fe2.8O4 NPs exhibits the highest r1 value. We can therefore conclude from Figure 7 that the MS value affects as well the r1 value, but this rule is not equivalent to the case of r2. Within a certain range of Ms values, r1 will increase along with the increase of Ms, but for Ms values exceeding this range, the r1 value becomes smaller. We introduce therefore another main value of the T1-weighted imaging contrast agent, namely the r2/r1 value (Figure 8a-b); it is generally believed that the smaller the r2/r1 value is, the more likely it is for the materials to perform as a T1-weighted contrast agent. The brightness of each contrast agent corresponds to its concentration (e.g., the 13 ACS Paragon Plus Environment


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best imaging concentration of Gd-DTPA is 0.47 mg/ml). Hence, we performed T1-weighted imaging of 7 nm ZnxFe3−xO4 NPs (x = 0/0.1/0.2/0.3/0.4) at different concentrations. According to the gray level histograms of the collected MRI datasets, the brightness ranking stands as follows: Zn0.2Fe2.8O4 NPs > Zn0.1Fe2.9O4 NPs > Zn0.3Fe2.7O4 NPs > Zn0.4Fe2.6O4 NPs. In the Ms value range of 45 to 67 emu/g, T1-weighted imaging is getting brighter with the same size of the NPs while Ms value is increasing. Another major factor affecting the contrast in T1-weighted imaging is the number of ions with magnetic moments that are exposed to the surface of the contrast agent. In Figure S7b, we can see that the T1-weighted imaging of 4 nm Zn0.2Fe2.8O4 NPs is the brightest, next is the 7 nm Zn0.2Fe2.8O4 NPs and the last is 10 nm Zn0.2Fe2.8O4 NPs under the same Fe concentration (0.8 mM). This is because the smaller the particle size and the larger the specific surface area of the particle, the more ions with magnetic moments are exposed. However, because the Ms value of 7 nm Zn0.2Fe2.8O4 NPs has a positive effect on T1-weighted imaging, the intensity of gray-level values in the case of T1-weighted imaging with 4 nm Zn0.2Fe2.8O4 and 7 nm sized Zn0.2Fe2.8O4 NPs is not very different. CONCLUSION In this experiment we have used an oleic acid/alcohol/water system to synthetize a series

of

7 nm

ZnxFe3−xO4

NPs

with

different

doping

concentrations

(x = 0/0.1/0.2/0.3/0.4) and Zn0.2Fe2.8O4 NPs with different particle sizes (4 nm, 7 nm and 10 nm), all of which were shown to exhibit good crystallinity. Further on, we performed a series of MRI experiments based on a method that involves the precise control of the two considered variables, size and doping content, in a principled manner: (1) T1- and T2-weighted relaxation and imaging tests of 7 nm ZnxFe3−xO4 NPs (x = 0/0.1/0.2/0.3/0.4) with different Ms values; (2) T1- and T2-weighted relaxation and imaging tests of Zn0.2Fe2.8O4 NPs with different particle sizes (4 nm, 7 nm and 10 nm). By using a series of complementary experimental characterization approaches 14 ACS Paragon Plus Environment

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(VSM, XRD, XPS and Mössbauer spectra), the zinc doping mechanism of the ZnxFe3−xO4 NPs was resolved and the optimum doping concentration for this material to be used as an MRI contrast agent was obtained (Zn0.2Fe2.8O4). Furthermore, this optimal concentration was used to generate the sample set of ZnxFe3−xO4 NPs with different particle sizes. Briefly, the Zn2+ doping mechanism of this system is: when x ≤ 0.2, the nonmagnetic Zn2+ ions tend to occupy the Fe3+Td site, and some Fe2+Oh ions will change into Fe3+Oh to keep the charge balance and oxygen stoichiometry 4, so the total magnetic moment is increased; when x ≥ 0.2, a part of the Zn2+ ions will replace the position of the Fe3+Td, but some of them tend to occupy the Fe2+Oh ions at higher Zn2+ doping concentration, so the total magnetic moment is decreased. We can therefore conclude that: (i) Ms is the main factor affecting T2-weighted imaging [with the increase of Ms , the r2 value increases, and the contrast agent is better suited to a T2-weighted imaging effect] (ii) In the T1-weighted imaging mode, r1 and r2/r1 values are not the main factors affecting the achievable contrast/brightness (iii) In the Ms value range of 45 to 67 emu/g, T1-weighted imaging under optimal imaging concentration is brighter upon an increase in the Ms value (in the case of particles of the same size). The regularity of MR imaging effects (T1-weighted imaging and T2-weighted imaging) is thus based on instrinsic physical properties of the material. Because their utility with respect to the use of ZnxFe3−xO4 NPs as MRI contrast agents, these conclusions serve as well as an optional guide for the development of subsequent ligands with high coordination of water, which can potentially be used to obtain more efficient MRI contrast agents in future. In addition, the presented approach can be easily adapted and used to analyze and optimize various other MRI contrast agents that take the form of magnetic NPs doped with divalent transition metal ions. AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] (Aiguo Wu) 15 ACS Paragon Plus Environment


*E-mail: [email protected] (Fang Yang) *E-mail: [email protected] (Tianxiang Chen) *E-mail: [email protected] (Liqiang Luo) ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (51803228, 61571278), National Key R&D Program of China (2018YFC0910601), Zhejiang Provincial Natural Science Foundation of China (LGF18H180017). And thanks very much for Dr. Shiyu Du’s and Diwei Shi’s support and help in theoretical concepts. CONFLICT OF INTEREST The authors declare no conflict of interest. ASSOCIATED CONTENT Supporting Information The supporting information is available free of charge on the ACS Publications website at DOI: Grain diameter distribution maps of ZnxFe3-xO4 (x=0.1/0.2/0.3/0.4) and Zn0.2Fe2.8O4 with different sizes (4 nm, 7 nm and 10 nm); TEM images of Fe3O4 NPs and Zn0.5Fe2.5O4 NPs; The SAED mode of 7 nm Zn0.2Fe2.8O4 NPs; The Mössbauer spectra and extracted Mössbauer parameters from the Mössbauer spectra at 300 K of Zn0.2Fe2.8O4 NPs with different sizes (4 nm/7 nm/10 nm); XPS Zn 2p spectra of 7 nm ZnxFe3−xO4 (x=0/0.1/0.2/0.3/0.4) NPs; T2-weighted imaging of 7 nm ZnxFe3-xO4 NPs (x=0.1/0.2/0.3/0.4); T1-weighted imaging of Zn0.2Fe2.8O4 NPs with different sizes (4 nm, 7 nm and 10 nm); T2-weighted imaging of Zn0.2Fe2.8O4 NPs with different sizes (4 nm, 7 nm and 10 nm) (PDF)

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REFERENCES (1) Jun, Y. W.; Lee, J. H.; Cheon, J. Chemical Design of Nanoparticle Probes for High-Performance Magnetic Resonance Imaging. Angew. Chem.-Int. Edit. 2008, 47, 5122−5135. (2) Na, H. B.; Song, I. C.; Hyeon, T. Inorganic Nanoparticles for MRI Contrast Agents. Adv. Mater. 2009, 21, 2133−2148. (3) Kim, J.; Kim, H. S.; Lee, N.; Kim, T.; Kim, H.; Yu, T.; Song, I. C.; Moon, W. K.; Hyeon, T. Multifunctional Uniform Nanoparticles Composed of a Magnetite Nanocrystal Core and a Mesoporous Silica Shell for Magnetic Resonance and Fluorescence Imaging and for Drug Delivery. Angew. Chem.-Int. Edit. 2008, 47, 8438−8441. (4) Choi, J. S.; Kim, S.; Yoo, D.; Shin, T. H.; Kim, H.; Gomes, M. D.; Kim, S. H.; Pines, A.; Cheon, J. Distance-Dependent Magnetic Resonance Tuning As a Versatile MRI Sensing Platform for Biological Targets. Nature Materials 2017, 16, 537−542. (5) Lee, J. H.; Huh, Y. M.; Jun, Y. W.; Seo, J. W.; Jang, J. T.; Song, H. T.; Kim, S.; Cho, E. J.; Yoon, H. G.; Suh, J. S.; Cheon, J. Artificially Engineered Magnetic Nanoparticles for Ultra-sensitive Molecular Imaging. Nature Medicine 2007, 13, 95−99. (6) Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-responsive Nanocarriers for Drug Delivery. Nature Materials 2013, 12 , 991−1003. (7) Bulte, J. W. M.; Kraitchman, D. L. Iron Oxide MR Contrast Agents for Molecular and Cellular Imaging. Nmr in Biomedicine 2004, 17, 484−499. (8) Liu, C.; Zou, B. S.; Rondinone, A. J.; Zhang, J. Chemical Control of Superparamagnetic Properties of Magnesium and Cobalt Spinel Ferrite Nanoparticles Through Atomic Level Magnetic Couplings. J. Am. Chem. Soc. 2000, 122 , 6263−6267. (9) Sun, S. H.; Zeng, H.; Robinson, D. B.; Raoux, S.; Rice, P. M.; Wang, S. X.; Li, G. X. Monodisperse MFe2O4 (M = Fe, Co, Mn) Nanoparticles. J. Am. Chem. Soc. 2004, 126 , 273−279. (10) Liu, J.; Bin, Y.; Matsuo, M. Magnetic Behavior of Zn-Doped Fe3O4 Nanoparticles Estimated in Terms of Crystal Domain Size. J. Phys. Chem. C. 2012, 116, 134−143. (11) Jang, J. T.; Nah, H.; Lee, J. H.; Moon, S. H.; Kim, M. G.; Cheon, J. Critical Enhancements of MRI Contrast and Hyperthermic Effects by Dopant-Controlled Magnetic Nanoparticles. Angew. Chem.-Int. Edit. 2009, 48, 1234−1238. (12) Byrne, J. M.; Coker, V. S.; Cespedes, E.; Wincott, P. L.; Vaughan, D. J.; Pattrick, R. A. D.; Van der Laan, G.; Arenholz, E.; Tuna, F.; Bencsik, M.; Lloyd, J. R.; Telling, N. D. Biosynthesis of Zinc Substituted Magnetite Nanoparticles With Enhanced Magnetic Properties. Adv. Funct. Mater. 2014, 24, 2518−2529. (13) Wen, M.; Li, Q.; Li, Y. Magnetic, Electronic and Structural Properties of ZnxFe3-xO4. Journal of Electron Spectroscopy and Related Phenomena 2006, 153, 65−70. (14) Liang, X.; Wang, X.; Zhuang, J.; Chen, Y.; Wang, D.; Li, Y. Synthesis of Nearly Monodisperse Iron Oxide and Oxyhydroxide Nanocrystals. Adv. Funct. Mater. 2006, 16, 1805−1813. (15) Verwey, E. J. W.; Heilmann, E. L. Physical Propertiles And Cation Arrangement of Oxides With Spinel Structure: Cation Arrangement in Spinels. Journal of Chemical Physics 1947, 15, 174−180. (16) Kolhatkar, A. G.; Jamison, A. C.; Litvinov, D.; Willson, R. C.; Lee, T. R. Tuning the Magnetic Properties of Nanoparticles. International Journal of Molecular Sciences 2013, 14, 15977−16009. (17) Nakashima, S.; Fujita, K.; Tanaka, K.; Hirao, K.; Yamamoto, T.; Tanaka, I. First-principles XANES Simulations of Spinel Zinc Ferrite With A Disordered Cation Distribution. Physical Review B



2007, 75, 1−8. (18) Jeyadevan, B.; Tohji, K.; Nakatsuka, K. Structure-Analysis of Coprecipitated ZnFe2O4 by Extended X-Ray-Absorption Fine-structure. Journal of Applied Physics 1994, 76, 6325−6327. (19) Oliver, S. A.; Harris, V. G.; Hamdeh, H. H.; Ho, J. C. Large Zinc Cation Occupancy of Octahedral Sites in Mechanically Activated Zinc Ferrite Powders. Applied Physics Letters 2000, 76, 2761−2763. (20) Chinnasamy, C. N.; Narayanasamy, A.; Ponpandian, N.; Chattopadhyay, K.; Guerault, H.; Greneche, J. M. Magnetic Properties of Nanostructured Ferrimagnetic Zinc Ferrite. Journal of Physics-Condensed Matter 2000, 12, 7795−7805. (21) Tanaka, K.; Makita, M.; Shimizugawa, Y.; Hirao, K.; Soga, N. Structure and High Magnetization of Rapidly Quenched Zinc Ferrite. J. Phys. Chem. Solids 1998, 59, 1611−1618. (22) Nakashima, S.; Fujita, K.; Tanaka, K.; Hirao, K. High Magnetization and The High-Temperature Superparamagnetic Transition With Intercluster Interaction in Disordered Zinc Ferrite Thin Film. Journal of Physics-Condensed Matter 2005, 17, 137−149. (23) Jha, A.; Kumar, N.; Sahni, M.; Srivastava, A.; Dwivedi, J.; Chaubey, S. Magnetization in Nanocrystalline PLD Zinc Ferrite Thin Films Deposited on Fused Quartz Substrate. Journal of Superconductivity and Novel Magnetism 2018, 31, 107−116. (24) Wu, W.; Wu, Z.; Yu, T.; Jiang, C.; Kim, W. S. Recent Progress on Magnetic Iron Oxide Nanoparticles: Synthesis, Surface Functional Strategies and Biomedical Applications. Science and Technology of Advanced Materials 2015, 16, 023501−023543. (25) Zhu, S.; Xu, X.; Rong, R.; Li, B.; Wang, X. Evaluation of Zinc-Doped Magnetite Nanoparticle Toxicity in The Liver and Kidney of Mice After Sub-chronic Intragastric Administration. Toxicology Research 2016, 5, 97−106. (26) Wang, X.; Li, Y. Monodisperse Nanocrystals: General Synthesis, Assembly, and Their Applications. Chemical Communications 2007, 28, 2901−2910. (27) Xie, W.; Guo, Z.; Gao, F.; Gao, Q.; Wang, D.; Liaw, B. S.; Cai, Q.; Sun, X.; Wang, X.; Zhao, L. Shape-, Size- and Structure-Controlled Synthesis and Biocompatibility of Iron Oxide Nanoparticles for Magnetic Theranostics. Theranostics 2018, 8, 3284−3307. (28) Yang, L.; Wang, Z.; Ma, L.; Li, A.; Xin, J.; Wei, R.; Lin, H.; Wang, R.; Chen, Z.; Gao, J. The Roles of Morphology on the Relaxation Rates of Magnetic Nanoparticles. ACS NANO 2018, 12, 4605− 4614. (29) Abareshi, M.; Goharshadi, E. K.; Zebarjad, S. M.; Fadafan, H. K.; Youssefi, A. Fabrication, Characterization and Measurement of Thermal Conductivity of Fe3O4 Nanofluids. J. Magn. Magn. Mater. 2010, 322, 3895−3901. (30) Tan, Y.; Zhuang, Z.; Peng, Q.; Li, Y. Room-Temperature Soft Magnetic Iron Oxide Nanocrystals: Synthesis, Characterization, and Size-dependent Magnetic Properties. Chem. Mater. 2008, 20, 5029 − 5034. (31) Bhavani, P.; Rajababu, C. H.; Arif, M. D.; Reddy, I. V. S.; Reddy, N. R. Synthesis of High Saturation Magnetic Iron Oxide Nanomaterials via Low Temperature Hydrothermal Method. J. Magn. Magn. Mater. 2017, 426, 459−466. (32) Pu, Y.; Tao, X.; Zeng, X.; Le, Y.; Chen, J. F. Synthesis of Co-Cu-Zn Doped Fe3O4 Nanoparticles With Tunable Morphology and Magnetic Properties. J. Magn. Magn. Mater. 2010, 322, 1985−1990. (33) Dobson, D. C.; Linnett, J. W.; Rahman, M. M. Mössbauer Studies of Charge Transfer Process in System ZnxFe3-xO4. J. Phys. Chem. Solids 1970, 31, 2727−2733. (34) Haggstrom, L.; Kamali, S.; Ericsson, T.; Nordblad, P.; Ahniyaz, A.; Bergstrom, L. Mössbauer and


Page 18 of 32

Page 19 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Magnetization Studies of Iron Oxide Nanocrystals. Hyperfine Interactions 2008, 183, 49−53. (35) Poulin, S.; Franca, R.; Moreau Belanger, L.; Sacher, E. Confirmation of X-Ray Photoelectron Spectroscopy Peak Attributions of Nanoparticulate Iron Oxides, Using Symmetric Peak Component Line Shapes. J. Phys. Chem. C

2010, 114, 10711−10718.

(36) Tan, P. Active Phase, Catalytic Activity, and Induction Period of Fe/Zeolite Material in Nonoxidative Aromatization of Methane. J. Catal. 2016, 338, 21−29. (37) Wuhn, M.; Joseph, Y.; Bagus, P. S.; Niklewski, A.; Puttner, R.; Reiss, S.; Weiss, W.; Martins, M.; Kaindl, G.; Woll, C. The Electronic Structure and Orientation of Styrene Adsorbed on FeO(111) and Fe3O4(111) - A Spectroscopic Investigation. J. Phys. Chem. B 2000, 104, 7694−7701. (38) Bhargava, G.; Gouzman, I.; Chun, C. M.; Ramanarayanan, T. A.; Bernasek, S. L. Characterization of The "Native" Surface Thin Film on Pure Polycrystalline Iron: A High Resolution XPS and TEM Study. Appl. Surf. Sci. 2007, 253, 4322−4329. (39) Dake, L. S.; Baer, D. R.; Zachara, J. M. Auger Parameter Measurements of Zinc-Compounds Relevant to Zinc Transport in The Environment. Surf. Interface Anal. 1989, 14, 71−75. (40) Wei, H.; Bruns, O. T.; Kaul, M. G.; Hansen, E. C.; Barch, M.; Wisniowska, A.; Chen, O.; Chen, Y.; Li, N.; Okada, S.; Cordero, J. M.; Heine, M.; Farrar, C. T.; Montana, D. M.; Adam, G.; Ittrich, H.; Jasanoff, A.; Nielsen, P.; Bawendi, M. G. Exceedingly Small Iron Oxide Nanoparticles as Positive MRI Contrast Agents. Proceedings of the National Academy of Sciences of the United States of America 2017, 114, 2325−2330. (41) De Leon-Rodriguez, L. M.; Martins, A. F.; Pinho, M. C.; Rofsky, N. M.; Sherry, A. D. Basic MR Relaxation Mechanisms and Contrast Agent Design. Journal of Magnetic Resonance Imaging 2015, 42, 545−565. (42) Kim, B. H.; Lee, N.; Kim, H.; An, K.; Park, Y. I.; Choi, Y.; Shin, K.; Lee, Y.; Kwon, S. G.; Na, H. B.; Park, J. G.; Ahn, T. Y.; Kim, Y. W.; Moon, W. K.; Choi, S. H.; Hyeon, T. Large-Scale Synthesis of Uniform and Extremely Small-Sized Iron Oxide Nanoparticles for High-Resolution T1 Magnetic Resonance Imaging Contrast Agents. J. Am. Chem. Soc. 2011, 133, 12624−12631. (43) Werner, E. J.; Datta, A.; Jocher, C. J.; Raymond, K. N. High-Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging. Angew. Chem.-Int. Edit. 2008, 47, 8568−8580. (44) Jun, Y. W.; Huh, Y. M.; Choi, J. S.; Lee, J. H.; Song, H. T.; Kim, S.; Yoon, S.; Kim, K. S.; Shin, J. S.; Suh, J. S.; Cheon, J. Nanoscale Size Effect of MagneticNanocrystals and Their Utilization for Cancer Diagnosis via Magnetic Resonance Imaging. J. Am. Chem. Soc. 2005, 127, 5732−5733. (45) Shen, Z.; Chen, T.; Ma, X.; Ren, W.; Zhou, Z.; Zhu, G.; Zhang, A.; Liu, Y.; Song, J.; Li, Z.; Ruan, H.; Fan, W.; Lin, L.; Munasinghe, J.; Chen, X.; Wu, A. Multifunctional Theranostic Nanoparticles Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for T1-Weighted Magnetic Resonance Imaging and Chemotherapy. ACS NANO 2017, 11, 10992−11004. (46) Zhou, Z.; Zhao, Z.; Zhang, H.; Wang, Z.; Chen, X.; Wang, R.; Chen, Z.; Gao, J. Interplay between Longitudinal and Transverse Contrasts in Fe3O4 Nanoplates with (111) Exposed Surfaces. ACS NANO 2014, 8, 7976−7985. (47) Lauffer, R. B. Paramagnetic Metal-Complexes as Water Proton Relaxation Agents for NMR Imaging-Theory and Design. Chem. Rev. 1987, 87, 901−927.



Figure 1. TEM micrographs: a)-d) 7 nm ZnxFe3-xO4 NPs with x = 0.1/0.2/0.3/0.4, respectively; c)-g) Zn0.2Fe2.8O4 NPs with size of 4 nm, 7nm and 10nm, respectively; (h) high-resolution TEM image of single 7 nm Zn0.2Fe2.8O4 NPs and the inset, depicting SAED mode (see Figure S4 in Supporting Information).


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Figure 2. Powder X-ray diffraction spectra at 300K: a) XRD patterns displaying the peaks obtained for ZnxFe3-xO4 NPs (x = 0/0.1/0.2/ 0.3/0.4); b) Enlargement of the diffraction intensity from the (311) plane.



Figure 3. The Mössbauer spectra at 300 K: a)-e) 7 nm ZnxFe3-xO4 NPs (x = 0/0.1/0.2/0.3/ 0.4). The Mössbauer spectrum of sample Zn0.4 has the spectrum 1 (corresponding to superparamagnetism), spectrum 2 (corresponding to Td site) and spectrum 3 (corresponding to Oh site). Although the peaks are relatively weak, the software of the instrument has assigned the labels Td and Oh.


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Figure 4. VSM results at 300 K of: a) ZnxFe3-xO4 NPs (x = 0/0.1/0.2/0.3/0.4) with different Zn2+ contents at 300 K. b) Curves normalized by Ms of Fe3O4; c) Zn0.2Fe2.8O4 NPs with different sizes (4 nm/7 nm/10 nm). d) Photograph showing that the Zn0.2Fe2.8O4 (7 nm) NPs dispersed in ethanol before and after magnetic field (30 s).



Scheme 1. a) The distribution of Td and Oh sites in the crystal structure of Fe3O4. b) In the oleic acid/alcohol/water system, the doping mechanism of Zn2+ doping in different concentration ranges and the change of total magnetic moment were studied.


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Figure 5. XPS Fe 2p spectra at 300 K and peak fitting analysis of: a) Fe3O4 NPs; b) 7 nm ZnxFe3−xO4 NPs (x=0/0.1/0.2/0.3/0.4) NPs.



Figure 6. Transverse relaxivities at 300 K of: a) 7 nm ZnxFe3−xO4 NPs (x = 0/0.1/0.2/0.3/0.4), b) corresponding r2 values for each sample. c) Zn0.2Fe2.8O4 NPs with different sizes (4 nm, 7 nm and 10 nm, respectively), d) corresponding r2 values for each differently sized sample.


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Figure 7. Longitudinal relaxivities at 300 K of: a) 7 nm ZnxFe3−xO4 NPs (x = 0.1/0.2/0.3/0.4), and the corresponding r1 values for each sample are shown in panel b). c) Zn0.2Fe2.8O4 NPs with different sizes (4 nm, 7 nm and 10 nm, respectively), and the corresponding r1 values for each sample are shown in panel d).



Figure 8. r1 values and r2/r1 values at 300 K of: a) 7 nm ZnxFe3−xO4 NPs (x = 0.1/0.2/0.3/0.4) NPs, and b) Zn0.2Fe2.8O4 NPs with different sizes (4 nm, 7 nm and 10 nm, respectively). c) The gray value curves of T1-weighted imaging of different concentrations of 7 nm ZnxFe3−xO4 NPs (x = 0.1/0.2/0.3/0.4) NPs. d) is the brightest T1-weighted imaging of 7 nm ZnxFe3−xO4 NPs (x = 0.1/0.2/0.3/0.4) NPs. T1-weighted imaging: using the fast acquisition interleaved spin echo (TR = 500 ms; TE = 6.47 ms) at 1.5 T in HwaMei Hospital, University of Chinese Academy of Sciences.


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Table 1. Synthesis conditions for the ZnxFe3-xO4 NPs with different zinc doping concentration (x=0/0.1/0.2/0.3/0.4/0.5) and different particle size (4 nm/7 nm/10 nm). Sample

Fe2+

Zn2+

Oleic

Ethanol

NaOH

H2O

Reaction

Reaction

Diameter

Name

/mM

/mM

acid/mL

/mL

/g

/ml

Temperature

time/h

/nm

/℃ Fe3O4

2

0

10

10

1

20

230

15

7

Zn0.1Fe2.9O4

1.73

0.267

10

10

1

20

230

15

7

Zn0.2Fe2.8O4

1.73

0.534

10

10

1

20

230

15

7

Zn0.3Fe2.7O4

1.73

0.801

10

10

1

20

230

15

7

Zn0.4Fe2.6O4

1.73

1.068

10

10

1

20

230

15

7

Zn0.5Fe2.5O4

1.73

1.335

10

10

1

20

230

15

—

Zn0.2Fe2.8O4

1.73

0.534

10

10

1

20

230

8

4

Zn0.2Fe2.8O4

1.73

0.534

10

10

1

20

230

20

10



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Table 2. Extracted Mössbauer parameters from the Mössbauer spectra of the 7 nm ZnxFe3−xO4 NPs (x = 0/0.1/0.2/0.3/0.4). ( IS is isomer shift, Bhf is hyperfine field, QS is quadrupole splitting, and Γ/2 is half-linear width).

Sample Name Fe3O4

Zn0.1Fe2.9O4

Zn0.2Fe2.8O4

Zn0.3Fe2.7O4

Zn0.4Fe2.6O4

Site

Bhf

IS

QS

Γ/2

Td

(KOe) 490.52

(mm/s) 0.38

(mm/s) 0

(mm/s) 0.15

Oh

462.71

0.75

0.14

0.4

Td

464.68

0.59

-0.21

0.4

Oh

420.35

0.86

-0.06

0.38

Td

471.94

0.39

-0.06

0.44

Oh

418

0.61

0

0.54

Td

449.2

0.51

0

0.52

Oh

379.5

0.49

0.28

0.27

Td

420.88

0.76

-0.17

1.37

Oh

211.55

1.06

0.04

0.49


Page 31 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3. Fe peak and Zn peak energies of ZnxFe3−xO4 NPs (x = 0/0.1/0.2/0.3/0.4). Sample Name

Fe 2p3/2 Position /eV

Fe 2p1/2 Position /eV

Zn 2p3/2 Position /eV

Zn 2p1/2 Position /eV

Fe3O4 Zn0.1Fe2.9O4 Zn0.2Fe2.8O4 Zn0.3Fe2.7O4 Zn0.4Fe2.6O4

710.755 710.951 711.095 711.131 711.250

724.247 724.832 724.847 724.882 724.915

— 1021.62 1021.65 1021.63 1021.64

— 1044.73 1044.72 1044.74 1044.76



ToC image:


Page 32 of 32

Precisely tuning the contrast properties of ZnxFe3 ... - ACS Publications

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