PEGylated GdF3:Fe Nanoparticles as Multimodal ... - ACS Publications

May 30, 2017 - challenging. In this work, biocompatible PEGylated GdF3:Fe nanoparticles. (PEG-GdF3:Fe NPs) were reasonable designed and synthesized as...
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PEGylated GdF3:Fe Nanoparticles as Multimodal T1/T2‑Weighted MRI and X‑ray CT Imaging Contrast Agents Lile Dong,†,‡ Peng Zhang,∥ Pengpeng Lei,†,§ Shuyan Song,† Xia Xu,†,§ Kaimin Du,†,‡ Jing Feng,*,† and Hongjie Zhang*,† †

State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China ‡ University of Science and Technology of China, Hefei 230026, China § University of Chinese Academy of Sciences, Beijing 100049, China ∥ Department of Radiology, The Second Hospital of Jilin University, Changchun 130041, China S Supporting Information *

ABSTRACT: Contrast agents for multimodal imaging are in high demand for cancer diagnosis. To date, integration of T1/T2-weighted magnetic resonance imaging (MRI) and X-ray computed tomography (CT) imaging capabilities in one system to obtain an accurate diagnosis still remains challenging. In this work, biocompatible PEGylated GdF3:Fe nanoparticles (PEG-GdF3:Fe NPs) were reasonable designed and synthesized as multifunctional contrast agents for efficient T1/T2-weighted MRI and Xray CT multimodal imaging. Owing to the enhanced permeability and retention effect in vivo, strong T1 contrast, evident T2 contrast, and X-ray CT signals in a tumor lesion can be observed after intravenous injection of PEG-GdF3:Fe NPs. Therefore, PEG-GdF3:Fe NPs could be used as potential multimodal contrast agents for cancer diagnosis. KEYWORDS: PEG-GdF3:Fe NPs, T1/T2-weighted MRI, X-ray CT imaging, multimodal of diagnosis of some incurable diseases.14 Unfortunately, the artifacts from calcification, bleeding, or metal deposits greatly reduce the efficiency of diagnosis and the lesion detection rate, leading to a serious impact on the quality of MRI.8−10,15,16 One way to overcome the limitation is T1 and T2 dual-mode MRI. MRI can provide images with excellent soft-tissue details. Whereas CT imaging can provide high 3D resolution information of bone and calcifications on the basis of the different X-ray absorptions of the tissues.17−21 Routine CT imaging contrast agents, such as iobitridol, can effectively enhance X-ray attenuation at the lesion so that they can illustrate the morphology and extent of the lesion more comprehensively. However, in recent reports it has been shown that iobitridol required to be administered at a high dosage and the low K-edge of iodine may produce an adverse effect that increases the burden of patients.12,13,22−24 Therefore, novel multifunctional and biocompatible contrast agents have emerged as ideal contrast agents for reducing the possibility of disease misdiagnosis.25−29 An ideal contrast agent should fulfill the following criteria: (1) multimodal imaging capability,

1. INTRODUCTION Until now, diagnostic techniques, including magnetic resonance imaging (MRI), ultrasound imaging, X-ray computed tomography (CT) imaging, optical fluorescence imaging, and photoacoustic imaging, have offered immense opportunities in the fight against cancer with the development of molecular imaging.1−4 MRI and X-ray CT imaging have been widely applied in the detection and diagnosis of clinical diseases due to the advantages of high resolution and noninvasiveness.5−7 In practical terms, the contrast agents could raise the sensitivity and visibility of MRI and X-ray CT imaging to achieve accurate diagnosis. MRI contrast agents based on longitudinal relaxivity (r1) and transverse relaxivity (r2) are classified as T1- and T2weighted contrast agents. Usually, paramagnetic compounds are T1 contrast agents, such as gadolinium(III) chelates, NaGdF4:Yb3+, Er3+/NaGdF4 core/shell upconversion nanoparticles, and GdF3 NPs.8−10 In this regard, Gd3+-containing compounds can serve as T1-weighted MRI contrast agents because Gd3+ possesses seven unpaired electrons that may effectively induce longitudinal relaxation of water protons.11 In contrast, T2-weighted MRI contrast agents are mainly based on Fe3O4 materials, which have large magnetization values.12,13 T1 contrast imaging reveals high three-dimensional (3D) softtissue resolution, whereas T2 contrast imaging was used to distinguish normal tissues and lesions, improving the accuracy © 2017 American Chemical Society

Received: March 29, 2017 Accepted: May 30, 2017 Published: May 30, 2017 20426

DOI: 10.1021/acsami.7b04438 ACS Appl. Mater. Interfaces 2017, 9, 20426−20434

Research Article

ACS Applied Materials & Interfaces

Figure 1. (a) Schematic illustration of the synthesis of PEG-GdF3:Fe NPs; (b) TEM image (inset: high-resolution TEM image); (c) XRD pattern; (d) EDX; (e) Fe 2p XPS spectra of PEG-GdF3:Fe NPs. 2.2. Preparation of PEG-GdF3:Fe NPs. PEG-GdF3:Fe NPs were synthesized through the hydrothermal approach. Typically, 0.6 g of PEG was mixed with 15 mL of EG under stirring to form a clear solution. Then, a 5 mL solution containing 0.8 mmol GdCl3·6H2O and 0.2 mmol FeCl3·6H2O was added to the above solution. Subsequently, 10 mL of EG containing a stoichiometric amount of NH4F was dropped slowly into the mixture. After stirring for 30 min, the mixture was transferred into a 50 mL Teflon-lined autoclave, which was operated at 200 °C for 10 h. After that, PEG-GdF3:Fe NPs were collected by centrifugation and washed with H2O. Finally, the obtained PEG-GdF3:Fe NPs were dispersed in H2O for further use. 2.3. Characterization. The phases of the PEG-GdF3:Fe NPs were determined by powder X-ray diffraction (XRD, D8 ADVANCE; Bruker). Transmission electron microscopy (TEM) was performed on a FEI Tecnai G2 microscope (200 kV). The composition of the samples was analyzed with an energy-dispersive X-ray (EDX) detector on a field-emission scanning electron microscope (S-4800; Hitachi). X-ray photoelectron spectroscopy (XPS) of the PEG-GdF3:Fe NPs was carried out on a VG ESCALAB MKII spectrometer. Thermogravimetric analysis was carried out with a NETZSCH STA 449F3 instrument. Inductively couple plasma mass spectrometry (ICPMS) was carried out on an ELAN 9000/DRC. The hydrodynamic size distribution of the NPs was measured using a Malvern Zetasizer Nano ZS90.

(2) high contrast efficiency, (3) high biocompatibility, and (4) a facile synthesis process. Herein, we used a facile method to construct a new T1/T2weighted MRI and X-ray CT imaging contrast agent by doping Fe3+ ions in a GdF3 matrix. PEGylated GdF3:Fe NPs (PEGGdF3:Fe NPs) possess excellent biocompatibility and hydrophilicity due to the existing PEG as the capping agent.30,31 It is found that the PEG-GdF3:Fe NPs, with a low cytotoxicity, can simultaneously enhance the positive T1 contrast and negative T2 contrast efficiencies in vitro and in vivo. Additionally, compared with iobitridol, PEG-GdF3:Fe NPs show brighter contrast on CT imaging, ascribed to the relatively high X-ray absorption coefficient of Gd3+ ions,32,33 which is able to reduce the dosage and adverse effect.

2. EXPERIMENTAL SECTION 2.1. Chemicals. Analytical grade GdCl3·6H2O (99.99%), FeCl3· 6H2O (99.99%), and methyl thiazolyl tetrazolium were purchased from Aladdin Reagents. NH4F (99.99%), ethylene glycol (EG, 99%), and poly(ethylene glycol) (PEG, MW = 4000) were purchased from Beijing Chemical Reagent. Lobitridol was purchased from Guerbet (France). 20427

DOI: 10.1021/acsami.7b04438 ACS Appl. Mater. Interfaces 2017, 9, 20426−20434

Research Article

ACS Applied Materials & Interfaces

Figure 2. (a) Viability of HeLa cells after treating with different concentrations of PEG-GdF3:Fe NPs; the viability was obtained by the MTT assay. (b) Cellular uptake assay of Fe with different concentrations of PEG-GdF3:Fe NPs. (c) Histological changes in the heart, liver, spleen, lung, and kidney of the normal mouse 2 weeks after intravenous injection of a PEG-GdF3:Fe NP solution. The control shows organ images of a mouse without injection of the PEG-GdF3:Fe NP solution. 2.9. In Vitro and in Vivo T1 and T2 Dual-Mode MRI. PEGGdF3:Fe NP solutions (0.5 mL) of various concentrations were prepared for in vitro T1 and T2 dual-mode MRI on a 1.5 T clinical MRI scanner, and the corresponding longitudinal and transverse relaxation times of the NPs were recorded on a Huantong 1.5 T MRI scanner (Shanghai, China). In vivo T1 and T2 dual-mode MRI was also performed on a 1.5 T clinical MRI scanner. We performed MRI on tumor mice by intratumoral injection (50 μL of 0.294 mM [Gd + Fe] for T1-weighted MRI; 50 μL of 2 mM Fe for T2-weighted MRI) and intravenous injection of PEG-GdF3:Fe NPs (100 μL, 9.4 mM [Gd + Fe] for T1 and T2 dual-mode MRI). The parameters are as follows: repetition time = 865 ms (T1) or 3820 ms (T2), echo time = 12 ms (T1) or 87 ms (T2), matrices size = 256 × 256 pixels2, field of view (FOV) read = 59 × 100 mm2 (T1) or 60 × 100 mm2 (T2), and slice thickness = 2.2 mm. 2.10. In Vitro and in Vivo X-ray CT Imaging. PEG-GdF3:Fe NPs (1 mL) and iobitridol solution of different concentrations (Gd or I = 30, 15, 7.5, 3.75, 1.88, 0.94, 0.47, and 0 mg mL−1) were prepared for in vitro X-ray CT imaging. We performed X-ray CT imaging on mice with tumors by intratumoral injection of PEG-GdF3:Fe NPs (50 μL, 30 mg mL−1). We also performed X-ray CT imaging on normal mice by intravenous injection of PEG-GdF3:Fe NPs (100 μL, 30 mg mL−1, n = 3). CT imaging was performed on a Philips iCT 256 slice scanner, with the following parameters: 0.9 mm thickness; 0.99, pitch; 120 kVp, voltage; 300 mA, current; 350 mm, FOV; 0.5 s, gantry rotation time; and 158.9 mm s−1 (table speed). 2.11. In Vivo T1/T2-Weighted MRI and X-ray CT Imaging Simultaneously. We performed T1/T2-weighted MRI and CT imaging of the mice with tumors by injection of the PEG-GdF3:Fe NP solution (100 μL, 6.524 mg/mL) via the tail vein. The operating parameters are as the same as those described in Sections 2.9 and 2.10 for MRI and CT imaging, respectively.

2.4. Cytotoxicity Assay. The standard 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the cytotoxicity of PEG-GdF3:Fe NPs toward HeLa cells. Cells were cultured in 96-well cell culture plates (104 per well) for 24 h and then incubated with various concentrations of PEG-GdF3:Fe NPs (0, 19, 39, 78, 156, 313, 625, and 1250 μg mL−1) for another 24 h. After that, 10 μL of MTT solution (5 mg mL−1) was added into each well and incubated for an additional 4 h. Finally, the absorbance value at 570 nm was recorded using a microplate reader. 2.5. Cellular Uptake Assay. A total of 105 cells were seeded in 1 mL of medium in each well of a six-well plate for 24 h and incubated with various concentrations of PEG-GdF3:Fe NPs (200, 100, and 50 μg mL−1) for another 24 h. Then, the cells were washed three times with phosphate-buffered saline (PBS) (pH 7.4) and trypsinized. The cell suspensions were digested with HNO3 (1 mL, 10%, v/v), and the intracellular Fe concentration was determined by ICP-MS measurement. 2.6. Animal Experiments. Female Kunming mice were obtained from the Laboratory Animal Center of Jilin University (China). All in vivo experiments were conducted in strict adherence the criteria of the Regional Ethics Committee for Animal Experiments. The tumor models were established by subcutaneous injection of H22 cells in the left axilla of each Kunming mouse. The tumor size is allowed to reach around 200 mm3 for animal experiments. 2.7. Histological Assessment. A volume of 100 μL of the PEGGdF3:Fe NP solution (30 mg Gd/kg body weight, n = 3) was intravenously injected into the mice (the test group). The mice without injection of PEG-GdF3:Fe NPs form the control group (n = 3). The heart, liver, spleen, lung, and kidney were collected and stained with hematoxylin and eosin after 14 days. 2.8. Biodistribution. The PEG-GdF3:Fe NP solution (the same dosage as that in the histological assessment) was intravenously injected into the mice. The mice were euthanized at different times (0, 1, 3, 7, and 15 days). The heart, liver, spleen, kidney, and feces were dissolved with 10 mL of aqua regia, respectively. Then, the obtained solution was kept at 60 °C for 6 h. The content of Gd in the above organs and feces was analyzed by ICP-MS.

3. RESULTS AND DISCUSSION 3.1. Synthesis and Characterization. As illustrated in Figure 1a, PEG-GdF3:Fe NPs were synthesized by the hydrothermal method. TEM images indicate that PEGGdF3:Fe NPs are monodisperse with a high crystallinity 20428

DOI: 10.1021/acsami.7b04438 ACS Appl. Mater. Interfaces 2017, 9, 20426−20434

Research Article

ACS Applied Materials & Interfaces

Figure 3. (a) Linear relationship between 1/T1 and [Gd + Fe] concentrations; (b) linear relationship between 1/T2 and Fe concentrations; (c) in vitro T1-weighted MR images of PEG-GdF3:Fe NPs with varied [Gd + Fe] concentrations; (d) in vitro T2-weighted MR images of PEG-GdF3:Fe NPs with varied Fe3+ concentrations; (e) in vivo T1-weighted and (f) T2-weighted MR images of tumor-bearing mice after intratumoral injection of PEG-GdF3:Fe NPs at timed intervals (tumor, blue circles).

(Figure 1b and inset). The NPs are 51.9 ± 6.1 nm in length and 31.3 ± 3.5 nm in width (Figure S1, Supporting Information). As shown in Figure 1c, the XRD pattern of the PEG-GdF3:Fe NPs exhibits a pure orthorhombic phase of GdF3, which can absolutely match with the orthorhombic phase of GdF3 (JCPDS file no. 12-0788). Further, the diffraction peak shifts to the higher angle due to the substitution of Gd3+ ions by Fe3+ ions in GdF3 host lattice (Figure S2).34,35 EDX (Figure 1d) and XPS survey spectra (Figures 1e and S3) synergistically confirm the presence of F−, Fe3+, and Gd3+ in PEG-GdF3:Fe NPs. The EDX pattern reveals that the ratio of Gd/Fe is 5.5:1.0 in PEGGdF3:Fe NPs, and the XPS survey spectrum also reveals that the ratio of Gd/Fe is 5.6:1.0 on the surface of PEG-GdF3:Fe NPs. ICP-MS analysis of Gd and Fe indicates that the ratio of Gd/Fe is approximately 5.7:1.0. The ratio of Gd and Fe in the as-prepared NPs was higher than the ratio of the precursors, which may due to the substitution by Fe3+ ions with smaller ionic radii than that of Gd3+ ions in GdF3 host lattice.35 The EDX line-scanning profiles provide detailed information on the

distribution of Fe and Gd elements in PEG-GdF3:Fe NPs (Figure S4). These characterizations demonstrate that Fe3+ ions have been doped into the crystal lattice of the GdF3 matrix. Fourier transform infrared (FTIR) spectroscopy of PEGGdF3:Fe NPs confirms the presence of PEG (Figure S5).36,37 The mass percentage of PEG on the surface of the NPs accounts for 2.2% according to thermogravimetric analysis (Figure S6). Because of the PEG coated on the surface of the NPs, the PEG-GdF3:Fe NPs remained stable in water. The hydrodynamic size and morphology of PEG-GdF3:Fe NPs in water and PBS were monitored. The morphology of PEGGdF3:Fe NPs in water is not different from that in PBS as per TEM. However, the hydrodynamic size of PEG-GdF3:Fe NPs in water is smaller than that of PEG-GdF3:Fe NPs in PBS (Figure S7). This may imply that the NPs remained more stable in water than in PBS. Moreover, the PBS solution (pH 7.4) of PEG-GdF3:Fe NPs was subjected to week-long dialysis, and no free Fe3+ or Gd3+ ions in the PBS solution were detected. 20429

DOI: 10.1021/acsami.7b04438 ACS Appl. Mater. Interfaces 2017, 9, 20426−20434

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ACS Applied Materials & Interfaces

Figure 4. In vivo T1-weighted (a) and T2-weighted (b) MR images of tumor-bearing mice after intravenous injection of PEG-GdF3:Fe NPs at timed intervals (tumor, red circles; liver, ellipses; spleen, blue circles).

which is comparable to that of KGdF4 NCs (1.97 emu g−1).11 Then, the longitudinal (r1) and transverse (r2) relaxivities of the PEG-GdF3:Fe NPs were measured to be 3.3 and 36.0 mM−1 s−1, respectively, as can be seen in Figure 3a,b. For the routine MRI, the r2/r1 ratio is a key reference value: r2/r1 > 8 leads to a T2-dominated MRI contrast; in contrast, r2/r1 < 5 results in a T1-dominated MRI contrast.14,40 Although the r2/r1 ratio of the PEG-GdF3:Fe NPs is 10.2, which implies that the contrast agent is a T2-dominated contrast, r2 is much lower than that of Feridex (120 mM−1 s−1).12,41 This might be the reason why PEG-GdF3:Fe NPs can be used as T1 and T2 dual-mode MRI contrast agents, which is similar to the reported FeCo NPs (r2/ r1 = 9.2).42 Subsequently, with an increase in the concentration of PEG-GdF3:Fe NPs, brighter T1 signals and darker T2 signals could be observed under the T1-weighted (Figure 3c) and T2weighted MRI mode in vitro (Figure 3d), respectively. It is found that PEG-GdF3 NPs without Fe3+ could be used only as T1 contrast agents. As shown in Figure S11, concentrationdependent T1-positive signals could be observed under T1weighted MRI in vitro, and the corresponding r1 of the PEGGdF3 NPs was determined to be 0.3 mM−1 s−1. All of the above results demonstrate that PEG-GdF3:Fe NPs could be applied as T1 and T2 dual-mode MRI contrast agents through Fe3+ doping. On the basis of the inspiring results in vitro, we performed T1 and T2 dual-mode MRI on mice with tumors. As shown in Figure 3e, the tumor site showed strong positive enhancement in T1-weighted MRI after 30 min. In contrast, the tumor site showed negative contrast in T2-weighted MRI (Figure 3f). Then, the time-dependent biodistribution was tracked by T1 and T2 dual-mode MRI after intravenous injection of the mice with tumors. PEG-GdF3:Fe NPs could accumulate in tumor tissue during long circulation in the mice, which was attributed to enhanced permeability and the retention effect.36,43 From T1-weighted MRI in Figure 4a, it can be seen that the tumor tissues showed positive signal enhancement after 1.5 h of injection. After 2.5 h of injection, the tumor lesions showed

3.2. Biocompatibility Assessment. We conducted a standard MTT assay on HeLa cells to test the cytotoxicity of PEG-GdF3:Fe NPs. Remarkably, the results demonstrate that PEG-GdF3:Fe NPs display a low cytotoxicity even at high concentrations, as shown in Figure 2a. It is indicated that PEGGdF3:Fe NPs possess excellent biocompatibility in vitro. We estimated the intracellular NP uptake by ICP-MS measurements. The results showed that the cellular uptake of Fe was 11.22, 4.05, and 2.99 after incubation with the NPs at concentrations of 200, 100, and 50 μg/mL, respectively, which confirmed that PEG-GdF3:Fe NPs enter the cells (Figure 2b). Furthermore, we performed histological assessment to evaluate the biocompatibility of PEG-GdF3:Fe NPs in vivo. It can be seen from the main organs that there was no inflammatory lesion in the experimental and control groups (Figure 2c). The mice of the experimental and control groups showed a similar growth trend in body weight (Figure S8). To further investigate the metabolic pathway of PEG-GdF3:Fe NPs in vivo, the content of Gd in the main organs and feces at different time points were determined by ICP-MS (Figure S9). As shown in Figure S9, PEG-GdF3:Fe NPs mainly aggregate in the liver and spleen. After 15 days of injection, the detected Gd content in organs became lower, indicating that most of the PEG-GdF3:Fe NPs could be eliminated from the mouse through the hepatic-clearable excretion pathway, which is similar to that of MoS2/Bi2S3-PEG, Cu2−xS, and gadoliniumdoped iron oxide NPs in vivo.15,38,39 The above results demonstrated that PEG-GdF3:Fe NPs with a high biocompatibility and low cytotoxicity could be used as an available contrast agent for multimodal imaging. 3.3. In Vitro and in Vivo T1 and T2 Dual-Mode MRI. We first measured the field-dependent magnetization (M−H) curves of PEG-GdF3:Fe NPs (Figure S10). As shown, the mass magnetic susceptibility of the PEG-GdF3:Fe NPs is 11.84 × 10−5 emu Oe−1 g−1. The room temperature magnetization of the PEG-GdF3:Fe NPs is 2.38 emu g−1 (Gd + Fe) at 20 kOe, 20430

DOI: 10.1021/acsami.7b04438 ACS Appl. Mater. Interfaces 2017, 9, 20426−20434

Research Article

ACS Applied Materials & Interfaces

Figure 5. In vitro CT images (a) and CT values (b) of PEG-GdF3:Fe NPs and iobitridol solutions with different concentrations of Gd and I, respectively; (c) in vivo CT images of a tumor-bearing mouse before and after intratumoral injection (tumor, circles) of PEG-GdF3:Fe NPs: preinjection (i−iii) and postinjection (iv−vi); in vivo CT images of mice after intravenous injection of PEG-GdF3:Fe NPs at timed intervals: (d) heart, liver, and spleen; (e) liver, spleen, and kidney; (f) the corresponding 3D renderings.

similar signals compared to those in the preinjection images; the spleen appeared brighter and showed strong positive enhancement. From T2-weighted MRI in Figure 4b, it can be seen that the tumor lesions showed negative enhancement after 1.5 h of injection. A slight negative enhancement in the liver was also observed after 2.5 h of injection. Notably, the integration of T1/T2-weighted MRI modes in a simple nanoagent may potentially enhance the ability of discriminating

hypointense tissue during MRI. The above results indicate that PEG-GdF3:Fe NPs could serve as effective T1 and T2 dualmode MRI contrast agent for cancer diagnosis. 3.4. In Vitro and in Vivo X-ray CT Imaging. As shown in Figure 5a,b, PEG-GdF3:Fe NPs exhibit a stronger CT contrast signal than that of iobitridol in vitro. Furthermore, after intratumoral injection of PEG-GdF3:Fe NPs, the contrast signals of the CT images for the mice with tumors were 20431

DOI: 10.1021/acsami.7b04438 ACS Appl. Mater. Interfaces 2017, 9, 20426−20434

Research Article

ACS Applied Materials & Interfaces

Figure 6. In vivo CT images (a), T1-weighted MRI, (b) and T2-weighted MRI (c) of tumor-bearing mice after intravenous injection of PEG-GdF3:Fe NPs at timed intervals (tumor, blue circles; liver, ellipses; spleen, red circles).

T2 dual-mode MRI and CT imaging on using PEG-GdF3:Fe NPs as the contrast agents. The desirable results indicate that PEG-GdF3:Fe NPs have great potential as multifunctional contrast agents for multimodal imaging.

obviously enhanced, as shown in Figure 5c, revealing that PEGGdF3:Fe NPs can be used at a reduced dosage to enhance the contrast efficiently compared to that of clinical iobitridol. Then, the biodistribution was examined by tracking the CT imaging signals at timed intervals after intravenous injection of normal mice (Figures 5d−f and S12). An enhancement in the noticeable CT signal in the liver and spleen at 10 min could be clearly observed; it remained observable at 2 h. The contrast enhancement of the CT imaging signals was similar to that on MRI. One possible reason for the long-lasting contrast enhancement in the liver and spleen is the uptake of PEGGdF3:Fe NPs by macrophages and hepatocytes. The Hounsfield unit (HU) value in the liver and spleen decreased and in the intestinal tract, increased after 30 days (Figure S13), indicating that PEG-GdF3:Fe NPs may take a hepatic-clearable excretion pathway, which is in agreement with the results of biodistribution by ICP-MS. 3.5. In Vivo T1/T2-Weighted MRI and X-ray CT Imaging Simultaneously. Encouraged by the above results, we further evaluate the performance of PEG-GdF3:Fe NPs as MRI and CT imaging contrast agents. As exhibited in Figures 6a and S14, the tumor site, liver, and spleen showed significant signal enhancement in X-ray CT imaging after 2.5 h, which is consistent with the CT images in Figure 5d−f. As for T1weighted MRI in Figure 6b, the tumor site, liver, and spleen became brighter after injection for 2.5 h. We also observed that the tumor site, liver, and spleen became darker in the T2weighted MR images after injection for 2.5 h (Figure 6c). The above results demonstrate that PEG-GdF3:Fe NPs could serve as multifunctional contrast agents for T1/T2 dual-mode MRI and CT imaging.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.7b04438. Grain size distribution; enlarged XRD pattern; full XPS spectra; line-scanning profiles; FTIR spectroscopy; thermogravimetric analysis; TEM and hydrodynamic diameter distribution; body weight growth curves; biodistribution; field-dependent magnetization curves; in vitro T1-weighted MRI of PEG-GdF3 NPs; HU values of different organs at timed intervals; HU values of the intestinal tract; HU values of different organs (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel:+86 431 85262127. Fax: +86 431 85698041 (J.F.). *E-mail: [email protected] (H.Z.). ORCID

Hongjie Zhang: 0000-0001-5433-8611 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful for the financial aid from the National Natural Science Foundation of China (21371165, 21590794, 21521092, 21210001, and 51372242), the National Key Basic Research Program of China (2014CB643802), the Strategic Priority Research Program of the Chinese Academy of Sciences

4. CONCLUSIONS In summary, PEG-GdF3:Fe NPs with a high biocompatibility and low cytotoxicity have been prepared by the hydrothermal method. Significant contrast enhancement was obtained in T1/ 20432

DOI: 10.1021/acsami.7b04438 ACS Appl. Mater. Interfaces 2017, 9, 20426−20434

Research Article

ACS Applied Materials & Interfaces

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(XDB20000000), and the Youth Innovation Promotion Association of Chinese Academy of Sciences (2015181).

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DOI: 10.1021/acsami.7b04438 ACS Appl. Mater. Interfaces 2017, 9, 20426−20434