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Back to Journal »International Journal of Nanomedicine» Volume 16
Comparative study on the pro-inflammatory effects of γ-Fe2O3 NP and gadolinium dimeglumine on renal function
Authors: Xie Q, Wen Tao, Yang A, Zhang X, Chen B, Meng J, Liu J, Gu N, Xu H
Published on March 18, 2021, the 2021 volume: 16 pages 2271-2282
DOI https://doi.org/10.2147/IJN.S299004
Single anonymous peer review
Editor who approved for publication: Dr. Farooq A. Shiekh
Xie Qian,1,* Tao Wen,2,* Aiyun Yang,2 Xue Zhang,2 Bo Chen,3 Jie Meng,2 Jian Liu,2 Ning Gu,4 Haiyan Xu2 1Department of Nephrology, Peking University Third Hospital, Beijing, 100191, People's Republic of China; 2 Institute of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College School of Basic Medicine, Beijing 100005; 3 Institute of Materials Science and Devices, University of Science and Technology of Suzhou, Suzhou 215009; 4 State Key Laboratory of Bioelectronics, Jiangsu Biomaterials Key Laboratory of and Devices, School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, 210096, People’s Republic of China Beijing, 100005 Email [email protected] Ninggu State Key Laboratory of Bioelectronics, Jiangsu Province Key Laboratory of Biomaterials and Devices, School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, 210096, People’s Republic of China Email [email protected ] Background: Contrast-enhanced magnetic resonance imaging (MRI) is a powerful diagnostic tool for many diseases. In many cases, contrast agents are used repeatedly in order to monitor and evaluate disease progression. Objective: To study and compare the biological effects of high and multiple doses of γ-Fe2O3 nanoparticles (NP) and dimethylamine gadolinium (Gd-DTPA) on the kidneys of healthy mice. Methods: The γ-Fe2O3 NP coated with polydextrose sorbitol carboxymethyl ether with a hydrodynamic size of 68.2 nm and the clinically applied Gd-DTPA were applied to healthy mice, and high-dose intravenous administration was repeated. The xCELLigence real-time cell analysis (RTCA) S16 instrument was used to measure the cell viability of human umbilical vein endothelial cells (HUVEC) under high doses of these two contrast agents. The biological effects of γ-Fe2O3 NP and Gd-DTPA on the kidneys were obtained by using a biochemical automatic analyzer and a serum multi-pro-inflammatory factor kit. Perform histopathological and immunohistochemical analysis of kidney tissue. Results: It shows that the pro-inflammatory response caused by γ-Fe2O3 NPs is weaker than that of Gd-DTPA, and the levels of IL-1β, IL-6, IL-18, TNF-α, and C- are much lower. Reactive protein (CRP) and ferritin. At the same time, the biochemical indicators of γ-Fe2O3 NPs did not increase, while Gd-DTPA did. Conclusion: Compared with Gd-DTPA, γ-Fe2O3 NPs induce weaker pro-inflammatory effects, indicating better renal safety. Therefore, it is recommended that γ-Fe2O3 NPs should be a safer and optional choice when repeated enhanced MRI is required. Keywords: iron oxide nanoparticles, pro-inflammatory, cytokines, renal function
Contrast-enhanced magnetic resonance imaging (MRI) is a common and necessary tool that has been used clinically to diagnose various organ diseases, such as cancer, infection, or bleeding. 1 During the imaging process, a contrast agent is usually injected intravenously to enhance the visualization of the lesion. Gadolinium (Gd)-based contrast agent (GBCA) is currently the mainstream clinical MRI contrast agent. 2 However, there are concerns that patients with advanced renal insufficiency may have an increased toxicological risk of nephrogenic systemic fibrosis (NSF). Therefore, since April 2010, GBCA has been warned by the U.S. Food and Drug Administration (FDA) for its use in patients with renal impairment. Injury patient
Therefore, for patients with renal insufficiency, an optional MRI contrast agent is necessary. Iron oxide nanoparticles (NPs) have attracted a lot of research interest due to their influence on relaxation time, 5-8 and there is still a lot of research in nanomedicine, including cell targeting, labeling and separation, drug or gene delivery systems, and Hyperthermia. 9-14 There are two iron oxide nanoparticle products, namely ferumoxsil (Lumirems/Gastromarks) for oral administration and ferumoxide (Endorems/Feridexs) for intravenous injection, which have previously been approved by the FDA, but due to economic and safety issues Both products have been discontinued. 15-18 19 So far, the FDA has approved a Fe3O4 NPs drug Ferumoxytol for the treatment of iron deficiency anemia in chronic kidney disease, but warned that the drug has the risk of allergic reactions. drug. 20 It can be noted that when patients with various tumors or kidney transplants need MRI enhanced images, the drug is used off-label s, 21 implying that iron oxide nanoparticles have valuable potential in MRI imaging of patients with kidney disease. It is worth noting that the difference between GBCAs and iron oxide NPs has not been fully studied, especially the biological effects on the kidneys in the context of repeated dosing that is often required in clinical practice. For example, the researchers compared the interaction between a single injection of GBCAs and PEG-coated small-sized γ-Fe2O3 NP in healthy mice, examined the biodistribution and the effect on liver function, and showed that iron oxide NP has better safety and GBCA comparison; 22 and another group studied two comparisons in renal failure rat models, indicating that DSPE-PEG-coated γ-Fe2O3 NP may be used as a substitute for GBCA in patients with kidney disease. 23 It has been noted that repeated use of GBCA has proven to accumulate in organs, and the potential threats are warned by repeated administration. 24 However, the effect of repeated administration of GBCA and iron oxide NP on kidney function is still an open question. The purpose of this work is to compare the effects of γ-Fe2O3 NP coated with Glycose sorbitol carboxymethyl ether with a hydrodynamic size of 68.2 nm and clinically used GBCA gadolinium dimethylamine (Gd-DTPA). The drug regimen also focuses on the long-term effects of inflammation on the kidneys in terms of tissue and serum levels (plan 1). Option 1 Description of the process and content of the research in this work.
Option 1 Description of the process and content of the research in this work.
The reasons for the design of this study are as follows: First, as a routine diagnostic method, MRI may be repeated every few months or weeks to evaluate a patient’s disease progression or treatment effect. Secondly, although Gd-DTPA is considered safe for patients with normal renal function, there are still several reports of Gd retention and fibrotic reactions. 25-27 strongly indicate that Gd may cause kidney damage to normal kidneys in some people. Here we show that the serum renal function indicators (BUN, Scr and Cys-C) and blood inflammatory factors (IL-1β, IL-6, IL-18, TNF-α, CRP and ferritin) in the Gd-DTPA group are related to γ -Fe2O3 NP increased significantly compared with the control group. Histopathological analysis of mouse kidneys also showed that γ-Fe2O3 NP is safer than Gd-DTPA, and repeated high-dose intravenous injections.
Gd-DTPA was purchased from Bayer Pharma AG (Germany). Reference 28 The normal saline for stroke was purchased from Peking Union Medical College Hospital. The iron oxide nanoparticles (γ-Fe2O3 NPs) coated with polydextrose sorbitol carboxymethyl ether were synthesized by the AC magnetic field induction method.
Observe the morphology of γ-Fe2O3 NP by transmission electron microscope (JEOL JEM-2100). Elemental analysis was performed on a field emission scanning electron microscope (FESEM, Hitachi S-4800, Tokyo, Japan) with energy dispersive X-ray (EDX). The hydrodynamic diameter and Zeta potential of γ-Fe2O3 NP are measured by Zetasizer Nano ZS90 analyzer (Malvern instrument).
Both primary human umbilical vein endothelial cells (HUVEC) and endothelial cell culture medium were purchased from ScienCell Research Laboratories (San Diego, CA). Cells are grown on cell culture plates and cultured in a 37°C, 5% CO2 humidified incubator.
The xCELLigence real-time cell analysis (RTCA) S16 instrument (ACEA Biosciences, USA) was used for the experiment, which was placed in an incubator at 37 °C and 5% CO2. A gold microelectrode embedded in a 16-well plate (E-plate 16 PET, ACEA Biosciences, USA) was used for cytotoxicity experiments. For HUVEC, cells are seeded at a density of 1×104 cells/well. Record the impedance at 15-minute intervals. Different concentrations of nanomaterials were added to the culture at 5 hours and recorded for 96 hours.
6-week-old female Balb/c mice were raised under specific pathogen-free conditions in the Experimental Animal Center of the Institute of Basic Medicine, Chinese Academy of Medical Sciences (Beijing, China). The mice were fed in a 12:12-hour light-dark cycle in a temperature-controlled animal room. All mice have unlimited access to a standard commercial laboratory diet. All mice were kept in a sterile animal room for 1 week before the experiment. The conduct and approval of animal experiments comply with the regulations of the Standing Committee of Animal Experiments of the Chinese Academy of Medical Sciences. On the first day, all mice were stratified by body weight and then randomly grouped, including the control group (normal saline), the γ-Fe2O3 NP group and the Gd-DTPA group (n=3). The dose of γ-Fe2O3 NP is 20 mg/kg (4 mg/mL) per mouse, and the dose of Gd-DTPA is 234.5 mg/kg (46.9 mg/mL) per mouse. Contrast agents are given on days 1-4, 7 and 10. All contrast agents are dissolved in saline. The dosing volume for each injection is 100 μL.
On the 17th day after the first injection, the mice were sacrificed. Serum samples were collected by centrifugation at 4°C. Blood urea nitrogen (BUN), serum creatinine (Scr), cystatin-c (Cys-C), C-reactive protein (CRP) and ferritin were measured with a biochemical automatic analyzer (AU5800, Beckman Coulter, USA). The mouse multi-factor detection kit (MCYTOMAG-70, EMD Millipore) was used to determine the serum levels of IL-6, IL-1β and TNF-α. IL-18 was measured using mouse ELISA kit (EMC011, eBioscience).
The kidneys of the mice were harvested, weighed and fixed in 10% neutral buffered formalin. Paraffin sections were stained with hematoxylin and eosin (HE) and Mason's trichrome dye (BA-4079A, BASO, China). Tumor necrosis factor α (TNF-α) and transforming growth factor-β (TGF-β) staining were also performed by immunohistochemical analysis. In short, the slides were dewaxed and then used for antigen retrieval in EDTA, pH = 8.0 (Servicebio, Wuhan, China) using a microwave oven. TNF-α (1: 300, ab92486, Abcam), TGF-β (1: 200, 19245T, CST, Cambridge, UK) and α-smooth muscle actin (α-SMA) (1: 200, ab5694, Abcam) Incubate overnight, and then incubate HRP-labeled goat anti-rabbit IgG (H+L) (PV-6001, Beijing Zhongshan Biotechnology Co., Ltd.) for 50 minutes at room temperature. The photo was taken by Nanozoomer (Hamamatsu, Japan). Kidney histology analysis was semi-quantitatively evaluated by two pathologists with more than 10 years of clinical experience. They were blind to the treatment group and scored the samples on a scale of 0-5 (0, normal histology; 1, mild Injury; 2, mild injury; 3, moderate injury; 4, severe injury).
Unless otherwise specified, all experiments are repeated at least 3 times, and quantitative data are expressed as mean ± standard deviation (SD). Use SPSS software (SPPS 20.0) to determine statistical significance and indicate it in the corresponding legend. As shown in the figure, p-values below 0.05 are considered statistically significant.
In this study, two MRI contrast agents were studied. The molecular formula of Gd-DTPA is shown in Figure 1A. For the γ-Fe2O3 NP, Fe atoms were detected in the EDX measurement (Figure 1B), and the insert shows a transmission electron microscope (TEM) image of the γ-Fe2O3 NP with a nucleus diameter of approximately 10 nm. The results obtained from dynamic light scattering (DLS) show that the particle size distributions in ddH2O and CM are narrow, and the average hydrodynamic diameters of γ-Fe2O3 NP in ddH2O are 68.2 ± 1.3 nm and 55.1 ± 0.9 nm, respectively. CM, respectively. The Zeta potential of γ-Fe2O3 NP is -26.4 ± 1.2 mV in ddH2O and -7.9 ± 0.6 mV in CM (Figure 1C). The decrease in negative charge is attributed to protein adsorption in CM. Figure 1 (A) Gd-DTPA formula, (B) γ-Fe2O3 NP energy dispersive X-ray (EDX) image. The inset shows the transmission electron microscope (TEM) image and (C) dynamic light scattering (DLS) size and zeta potential measurements of ddH2O and γ-Fe2O3 NP in the culture medium (CM).
Figure 1 (A) Gd-DTPA formula, (B) γ-Fe2O3 NP energy dispersive X-ray (EDX) image. The inset shows the transmission electron microscope (TEM) image and (C) dynamic light scattering (DLS) size and zeta potential measurements of ddH2O and γ-Fe2O3 NP in the culture medium (CM).
First, in order to evaluate the in vitro cytotoxicity of these two contrast agents, the growth curve of HUVEC exposed to high doses of Gd-DTPA or γ-Fe2O3 NP was measured by RTCA. The dimensionless parameter (cell index) corresponding to the relative change in the measured electrical impedance represents the cell state (the number of attached cells) in the RTCA system. 29 The values obtained from the RTCA system indicate that there is no significant difference in the cytotoxicity observed between the two contrast agents over a period of 96 hours of long incubation time (Figure 2). Figure 2 The growth curve of HUVEC cells in the presence of different concentrations of Gd-DTPA or γ-Fe2O3 NP. The black arrow indicates the time to apply the contrast agent. Error bars are the standard deviation of 3 parallel lines.
Figure 2 The growth curve of HUVEC cells in the presence of different concentrations of Gd-DTPA or γ-Fe2O3 NP. The black arrow indicates the time to apply the contrast agent. Error bars are the standard deviation of 3 parallel lines.
The in vivo effects of 6-week-old female balb/c mice were studied, and the contrast agent dose was equivalent to 5 times the clinically prescribed dose (γ-Fe2O3 was 1-7 mg/Kg, 46.9 mg/kg) /Kg for Gd-DTPA ) 30, 31 Histological analysis of mouse kidney tissue was performed with different specific histochemical stains 7 days after the last administration. During HE staining, a large number of cytoplasmic vacuoles were seen in the renal tubular cells of the Gd-DTPA group. By counting the cytoplasmic vacuoles in 10 fields of view, we found that there were 45, 48 and 126 cytoplasmic vacuoles in the control group, γ-Fe2O3 NP and Gd-DTPA groups, respectively. This indicates that injection of Gd-DTPA caused kidney damage, while few cytoplasmic vacuoles were observed in the control group and the γ-Fe2O3 NP group (Figure 3). Figure 3 Histopathological image of HE stained kidney tissue. The right column is the enlarged area of the rectangular box on the left column. The scale bar on the left is 250 μm, and the scale bar on the right is 50 μm. Dotted lines surround some typical cytoplasmic vacuoles.
Figure 3 Histopathological image of HE stained kidney tissue. The right column is the enlarged area of the rectangular box on the left column. The scale bar on the left is 250 μm, and the scale bar on the right is 50 μm. Dotted lines surround some typical cytoplasmic vacuoles.
Since organ damage usually leads to tissue fibrosis and chronic organ dysfunction, 32 Masson staining was performed on kidney tissue samples from different groups to check for tissue fibrosis. Masson staining in the Gd-DTPA group showed darker tissue staining, as indicated by the yellow arrow in Figure 4. The difference is that only a small amount of areas in γ-Fe2O3 were dyed in the blue NP group, and there was no significant difference compared with the control group. These indicate that the administration of Gd-DTPA induces obvious signs of tissue fibrosis. We next used anti-mouse α-SMA antibody (Figure 5) and anti-mouse TGF-β antibody (Figure 6) on kidney tissue to verify tissue fibrosis. The results showed that the tissues of the Gd-DTPA group showed stronger brown staining than the other two groups, indicating that fibrosis occurred; while there was no significant difference between the control group and the γ-Fe2O3 NP group. The results of statistical analysis of kidney histology are summarized in Table 1, semi-quantitatively performed by two experienced pathologists. The stained image and histochemical static analysis consistently showed that the administration of Gd-DTPA induced significant kidney damage, while the γ-Fe2O3 NP did not. Figure 4 Histopathological image of kidney tissue stained with Masson. The right column is the magnified area in the rectangular box on the left column. The scale bar on the left is 250 μm and the scale bar on the right is 50 μm. The arrow points to the pathological changes in the tissue. Figure 5 Histological image of α-SMA kidney tissue staining. The right column is the enlarged area in the left column rectangle. The left side of the scale bar is 250 μm, and the right side is 50 μm. The arrow points to the typical pathological changes in the tissue. Figure 6 Histological image of TGF-β stained kidney tissue. The right column is enlarged in the rectangle of the left column. The left side of the scale bar is 250 μm, and the right side is 50 μm. Table 1 Quantitative analysis of histopathological images
Figure 4 Histopathological image of kidney tissue stained with Masson. The right column is the magnified area in the rectangular box on the left column. The scale bar on the left is 250 μm, and the scale bar on the right is 50 μm. The arrow points to the pathological changes in the tissue.
Figure 5 Histological image of α-SMA kidney tissue staining. The right column is the enlarged area in the left column rectangle. The left side of the scale bar is 250 μm, and the right side is 50 μm. The arrow points to the typical pathological changes in the tissue.
Figure 6 Histological image of TGF-β stained kidney tissue. The right column is enlarged in the rectangle of the left column. The left side of the scale bar is 250 μm, and the right side is 50 μm.
Table 1 Quantitative analysis of histopathological images
The biochemical automatic analyzer, multi-factor detection and ELISA kit were used to determine the biochemical parameters and inflammatory factors related to renal function. The biochemical parameters of renal function include BUN, serum creatinine (Scr) and cystatin C (Cys-C). The results showed that, compared with the control, the administration of the two contrast agents did not affect the BUN level. Compared with the control group, the levels of Scr and Cys-C in the Gd-DTPA group increased significantly, while there was no change in the γ-Fe2O3 NP group (Figure 7). These two are accurate indicators of kidney function and are sensitive to kidney damage.33,34 Therefore, these results strongly indicate that multiple administrations of high-dose Gd-DTPA can cause mild to moderate kidney damage in healthy mice. Under the same injection protocol, γ-Fe2O3 NP does not affect renal function. These results are consistent with histopathological observations. Figure 7 The measurement of biochemical factors (BUN, Scr and Cys-C) in mouse serum. Data are from representative experiments (mean ± SD, n = 3). Use one-way analysis of variance for statistical analysis, and then perform least significant difference (LSD) post-test on BUN and Scr. Statistical analysis was performed using one-way analysis of variance, and then Dunnett-T3 post-hoc test was performed on Cys-C. *P <0.05, compared with the control group, #P <0.05 compared with the γ-Fe2O3 NP group.
Figure 7 The measurement of biochemical factors (BUN, Scr and Cys-C) in mouse serum. Data are from representative experiments (mean ± SD, n = 3). Use one-way analysis of variance for statistical analysis, and then perform least significant difference (LSD) post-test on BUN and Scr. Statistical analysis was performed using one-way analysis of variance, and then Dunnett-T3 post-hoc test was performed on Cys-C. *P <0.05, compared with the control group, #P <0.05 compared with the γ-Fe2O3 NP group.
Inflammatory factors are usually used to indicate the occurrence of acute inflammation. Here we use an ELISA kit to detect IL-1β, IL-6, IL-18, TNF-α and ferritin, and use a biochemical automatic analyzer to detect CRP in the blood. They are the most common inflammatory factors in the clinic. 35, 36 The results showed that the Gd-DTPA group triggered the highest levels of inflammatory factors (IL-1β, IL-6, IL-18, TNF-α and ferritin). The level of IL-1β in the γ-Fe2O3 NP group was lower than that of the Gd-DTPA group, but also higher than that of the control group. For other inflammatory factors (IL-6, IL-18, TNF-α, and ferritin), no differences were detected between the control group and the γ-Fe2O3 NP group (Figures 8 and 9). At the same time, the Gd-DTPA group showed the highest CRP level (Figure 9), although the difference between the groups was not significant. These results indicate that the inflammatory response induced by the administration of γ-Fe2O3 NP is significantly weaker than that of Gd-DTPA. Figure 8 Measurement of cytokine factors (IL-1β, IL-6, IL-18) in mouse serum. Data are from representative experiments (mean ± SD, n = 3). Statistical analysis was performed using one-way analysis of variance and least significant difference (LSD) post-hoc test *P <0.05, ** P <0.01 compared with the control group, #P <0.05 compared with the γ-Fe2O3 NP group. Figure 9 Measurement of TNF-α, CRP and ferritin in mouse serum. Data are from representative experiments (mean ± SD, n = 3). Use one-way analysis of variance for statistical analysis, and then perform a least significant difference (LSD) post-test for CRP. Statistical analysis of TNF-α and ferritin was performed using one-way analysis of variance and Dunnett-T3 post-hoc test. **P <0.01, compared with the control, #P <0.05, ##P <0.01, compared with the γ-Fe2O3 NP group.
Figure 8 Measurement of cytokine factors (IL-1β, IL-6, IL-18) in mouse serum. Data are from representative experiments (mean ± SD, n = 3). Statistical analysis was performed using one-way analysis of variance, followed by least significant difference (LSD) post-test *P <0.05, ** P <0.01 compared with the control group, #P <0.05 compared with the γ-Fe2O3 NP group.
Figure 9 Measurement of TNF-α, CRP and ferritin in mouse serum. Data are from representative experiments (mean ± SD, n = 3). Use one-way analysis of variance for statistical analysis, and then perform a least significant difference (LSD) post-test for CRP. Statistical analysis of TNF-α and ferritin was performed using one-way analysis of variance and Dunnett-T3 post-hoc test. **P <0.01, compared with the control, #P <0.05, ##P <0.01, compared with the γ-Fe2O3 NP group.
In this work, γ-Fe2O3 NP was coated with polydextrose sorbitol carboxymethyl ether. The average hydrodynamic diameter of γ-Fe2O3 NP is slightly different from that in the TEM image. This is because the highly hydrophilic coating increases the hydrodynamic layer on the surface of the nanoparticles. The Zeta potential of γ-Fe2O3 NP in ddH2O is -26.4 ± 1.2 mV, indicating its high dispersion stability. After interacting with the protein in the CM, the size is slightly reduced, and the Zeta potential becomes a potential close to that of pure CM (-6.8 ± 0.5 mV), indicating the stability of dispersion in biological liquids. Here, we have demonstrated that even in healthy mice, Gd-DTPA can cause moderately harmful changes to the kidneys through high-dose multiple administrations. On the contrary, from the perspective of pro-inflammatory effects, γ-Fe2O3 NP shows better compatibility than Gd-DTPA. These results indicate that although the two contrasts did not detect significant cytotoxicity in the long-incubation endothelial cell experiment, the two contrasts showed significantly different effects in vivo, which strongly suggests that in this case, Conventional cytotoxicity tests cannot well reflect the real situation in the body. In addition, even in healthy mice, repeated administration of Gd-DTPA can cause kidney damage, tissue fibrosis and inflammation. On the contrary, γ-Fe2O3 NP does not cause minor changes.
It has been recognized that only NP with a diameter of less than 6 nm can be cleared by the kidney, and 30-99% of administered NP will accumulate and segregate in the liver after administration. 37 Given that the average diameter is 68.2 ± 1.3 nm, γ-Fe2O3 NPs may pass through the hepatobiliary excretion pathway and may interact with hepatocytes. This is why it exhibits lower nephrotoxicity compared with GBCA. On the other hand, this function may bring potential risks to the liver. In our previous study, γ-Fe2O3 NPs were observed in the liver tissue of mice that were intravenously injected once a day for 7 days at the same high dose as this work. 38 We found that injection up-regulated the expression of CD31 and α-SMA in the liver, indicating that oxidative stress has occurred, which can be rescued by using active oxygen scavengers, mannitol or ascorbic acid. In addition, it is reported that iron oxide-based nanomaterials are slowly degraded in Kupffer cells and isolated in the mononuclear phagocyte system organs in a non-toxic form. 39,40 From the above aspects, prevention and treatment can be taken to overcome the limitations of clinical application.
For patients, no matter the disease itself, age, high blood pressure, diabetes, as well as drugs or treatment methods, many factors can cause kidney damage. Due to the above reasons, chronic kidney disease is highly prevalent worldwide, and most of them are silent and unknown, with no obvious indicators. 41 This may explain the serious side effects of Gd-DTPA that some “healthy” patients sometimes experience. 26,42 In view of the above, if there are any potential risk factors for kidney injury in advance, even patients with normal renal function should not be given Gd-DTPA as an MRI imaging contrast. Therefore, when it is necessary to perform repeated MRI-enhanced imaging scans on a patient, such as cancer and multifocal vascular disease, γ-Fe2O3 NP should be a safer and more important choice for clinicians to compare with MRI. Because the liver may have potential toxicity, preventive and therapeutic measures can be taken to overcome this possible limitation in clinical applications.
In conclusion, when high-dose repeated administration, Gd-DTPA can induce moderate renal injury by triggering inflammation that leads to fibrosis, while γ-Fe2O3 NP has no significant difference compared with the control group. It is very important for medical practitioners and patients to avoid side effects and track the problems of each measure during the diagnosis process. The results of this study provide extremely important tips for clinicians.
This study was conducted in accordance with the regulations of the Standing Committee of Animal Experiments of the Chinese Academy of Medical Sciences and was awarded the Institutional Animal Care and Use Committee (Institute of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China).
This work was supported by the National Key Research and Development Program (2017YFA0205504), the National Natural Science Foundation of China (81801771) and the CAMS Medical Science Innovation Fund (CIFMS 2016-I2M-3-004).
All authors who have contributed to data analysis, drafting, or revision of the article agree to the journal to which the article will be submitted, finally approve the version to be published, and agree to be responsible for all aspects of the work.
The authors report no conflicts of interest in this work.
1. Biegger P, Ladd ME, Komljenovic D. Multifunctional magnetic resonance imaging probe. Recent results of cancer research. 2020;216:189-226.
2. Fraum TJ, Ludwig DR, Bashir MR, Fowler KJ. Gadolinium contrast agents: comprehensive risk assessment. J Magn Reson imaging. 2017;46(2):338-353. doi:10.1002/jmri.25625
3. Rudnick MR, Wahba IM, Leonberg-Yoo AK, Miskulin D, Litt HI. The risks and options of using gadolinium contrast agents in CKD patients: a review. I am J kidney disease. 2020; S0272-6386(20):30926.
4. Todd DJ, Kay J. Gadolinium-induced fibrosis. Annu Rev Med. 2016; 67: 273-291. doi:10.1146/annurev-med-063014-124936
5. Wei H, Bruns OT, Kaul MG, etc. Very small iron oxide nanoparticles act as MRI-positive contrast agents. Proc Natl Acad Sci US A. 2017;114(9):2325-2330. doi:10.1073/pnas.1620145114
6. Avasthi A, Caro C, Pozo-Torres E, Leal MP, García-Martín ML. Magnetic nanoparticles act as MRI contrast agents. Top curry chemistry. 2020;378(3):40.
7. Deng LH, Jiang H, Lu FL, et al. PEGylated single crystal superparamagnetic iron oxide nanocomposite for MRI contrast agent size and PEG length control. Int J Nanomed. 2021; 16:201-211. doi:10.2147/IJN.S271461
8. Cai X, Zhu Q, Zeng Y, Zeng Q, Chen X, Zhan Y. Manganese oxide nanoparticles are used as MRI contrast agents in tumor multimodal imaging and treatment. Int J Nanomed. 2019; Volume 14(14): 8321–8344. doi:10.2147/IJN.S218085
9. Cardoso VF, Francesko A, Ribeiro C, Banobre-Lopez M, Martins P, Lanceros-Mendez S. Advances in magnetic nanoparticles for biomedical applications. Adv Healthc materials. 2018;7(5):1700845.
10. Hu Y, Mignani S, Majoral JP, Shen M, Shi X. Construction of a hybrid platform for tumor imaging and treatment based on iron oxide nanoparticles. Chem Soc Rev. 2018;47(5):1874–1900. doi:10.1039/C7CS00657H
11. Zhao S, Yu X, Qian Y, Chen W, Shen J. Multifunctional magnetic iron oxide nanoparticles: an advanced platform for cancer therapy. Therapeutics. 2020; 10(14): 6278-6309. doi:10.7150/thno.42564
12.zhi D, Yang T, Yang J, Fu S, Zhang S. Targeting strategies of superparamagnetic iron oxide nanoparticles in cancer treatment. Journal of Biomaterials. 2020; 102:13-34. doi:10.1016/j.actbio.2019.11.027
13. Xiao Y, Du J. Superparamagnetic nanoparticles for biomedical applications. J Mater Chem B. 2020;8(3):354-367. doi:10.1039/C9TB01955C
14. Jahangirian H, Kalantari K, Izadiyan Z, Rafiee-Moghaddam R, Shameli K, Webster TJ. An overview of small molecule and drug delivery applications using gold and iron nanoparticles. International J Nanomedicine. 2019; 14: 1633-1657. doi:10.2147/IJN.S184723
15. Wáng YXJ, Idée JM. Comprehensive literature update on the clinical research of superparamagnetic resonance iron oxide nanoparticles for magnetic resonance imaging. Quantitative imaging medical surgery. 2017; 7(1): 88-122. doi:10.21037/qims.2017.02.09
16. Bao Y, Sherwood JA, Sun Z. Magnetic iron oxide nanoparticles are used as T1 contrast agents for magnetic resonance imaging. J Mater Chem C. 2018;6(6):1280-1290. doi:10.1039/C7TC05854C
17. Azria D, Blanquer S, Verdier JM, Belamie E. Nanoparticles as a contrast agent for brain magnetic resonance imaging in the diagnosis of Alzheimer's disease. J Mater Chem B. 2017;5(35):7216-7237.
18. Wang Y-XJ. MRI contrast agents based on superparamagnetic iron oxide: current clinical applications. Quantitative imaging medical surgery. 2011;1(1):35–40. doi:10.3978/j.issn.2223-4292.2011.08.03
19. Frtús A, Smolková B, Uzhytchak M, etc. Analyze the mechanism of the interaction between iron oxide nanoparticles and cells: the path from failure to success in clinical applications. J Controlled release. 2020; 328: 59-77. doi:10.1016/j.jconrel.2020.08.036
20. Food and Drug Administration. Drug safety and availability-FDA drug safety communication. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warnings-and-changes-prescribing-instructions-decrease. Visited on March 30, 2015.
21. Nguyen KL, Yoshida T, Kathuria-Prakash N, etc. Multi-center safety and practice of using ferumoxytol for off-label diagnosis in MRI. radiology. 2019; 293: 554-564. doi:10.1148/radiol.2019190477
22. Chen R, Ling D, Zhao L, et al. Parallel comparative study of the toxicity of oxide nanoparticles and gadolinium-based T1 MRI contrast agent on mice. ACS nano. 2015; 9(12): 12425-12435. doi:10.1021/acsnano.5b05783
23. Weng Qiang, Hu Xiao, Zheng Jie, etc. Toxicology risk assessment of iron oxide nanoclusters and gadolinium-based T1 MRI contrast agent in rats with renal failure. ACS nano. 2019;13(6):6801–6812. doi:10.1021/acsnano.9b01511
24. Frenzel T, Apte C, Jost G, Schockel L, Lohrke J, Pietsch H. Quantification and evaluation of the chemical forms of residual gadolinium in the brain after repeated use of gadolinium contrast agents: a comparative study in rats. Invest in radio. 2017;52(7):396-404. doi:10.1097/RLI.0000000000000352
25. Kanda T, Oba H, Toyoda K, Kitajima K, Furui S. Gadolinium deposition in the brain after using a gadolinium contrast agent. Jpn J Radiol. 2016;34(1):3-9. doi:10.1007/s11604-015-0503-5
26. Roberts DR, Lindhorst SM, Wales CT, etc. There is a large amount of gadolinium deposits in the skin of patients with normal renal function. Invest in radio. 2016;51(5):280–289. doi:10.1097/RLI.0000000000000266
27. Mathur M, Jones JR, Weinreb JC. Gadolinium deposition and renal-derived systemic fibrosis: a primer for radiologists. Radiography. 2020; 40(1): 153–162. doi:10.1148/rg.2020190110
28. Chen Yi, Li Ya, Zhang X, etc. Effective synthesis of ferumoxytol induced by AC magnetic field. Mattlet. 2016; 170: 93-96. doi:10.1016/j.matlet.2016.02.006
29. Oberg HH, Peters C, Kabelitz D, Wesch D. Real-time cell analysis (RTCA), used to measure cell-killing activity against adhering tumor cells in vitro. Method enzyme. 2020; 631: 429-441.
30. Bose C, Megyesi JK, Shah SV, etc. Evidence indicates the role of iron in a mouse model of renal systemic fibrosis. Public Science Library One. 2015;10(8):e0136563. doi:10.1371/journal.pone.0136563
31. Toth GB, Varallyay CG, Horvath A, etc. Current and potential imaging applications of ferumoxytol in magnetic resonance imaging. Kidney International 2017;92(1):47–66. doi:10.1016/j.kint.2016.12.037
32. Mack M. Inflammation and fibrosis. Matrix organisms. 2018; 68-69: 106-121.
33. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019;394(10212):1949-1964. doi:10.1016/S0140-6736(19)32563-2
34. Bagshaw SM, Bellomo R. The role of Cystatin C in acute kidney injury. Curr Opin Crit Care. 2010;16(6):533-539. doi:10.1097/MCC.0b013e32833e8412
35. Prieto-Moure B, Lloris-Carsi JM, Belda-Antoli M, Toledo-Pereyra LH, Cejalvo-Lapena D. Allopurinol protects against renal ischemia by down-regulating TNF-α, IL-1β and IL-6 responses effect. J Invest Surg. 2017;30(3):143–151. doi:10.1080/08941939.2016.1230658
36. Wu Y, Potempa LA, El Kebir D, Filep JG. C-reactive protein and inflammation: conformational changes affect function. Biochemistry 2015;396(11):1181-1197.
37. Zhang YN, Poon W, Tavares AJ, Mc Gilvray ID, Chan WC. Nanoparticle-liver interaction: cellular uptake and hepatobiliary elimination. J Controlled release. 2016; 240: 332-348. doi:10.1016/j.jconrel.2016.01.020
38. Wen T, Du L, Chen B, et al. Iron oxide nanoparticles induce reversible endothelial-mesenchymal transition in vascular endothelial cells at acute non-cytotoxic concentrations. Part of the fiber poison. 2019;16(1):30. doi:10.1186/s12989-019-0314-4
39. Jain TK, Reddy MK, Morales MA, Leslie-Pelecky DL, Labhasetwar V. Biodistribution, clearance and biocompatibility of iron oxide magnetic nanoparticles in rats. Moore Pharmaceuticals. 2008;5(2):316-327. doi:10.1021/mp7001285
40. Levy M, Luciani N, Alloyeau D, etc. Long-term in vivo biotransformation of iron oxide nanoparticles. biomaterials. 2011;32(16):3988-3999. doi:10.1016/j.biomaterials.2011.02.031
41. Chen TK, Knicely DH, Grams ME. Diagnosis and management of chronic kidney disease: a review. J Am Med Assoc. 2019;322(13):1294–1304. doi:10.1001/jama.2019.14745
42. Semelka RC, Commander CW, Jay M, Burke LM, Ramalho M. Subjects with normal renal function inferred gadolinium toxicity: 4 cases reported. Invest in radio. 2016;51(10):661–665. doi:10.1097/RLI.0000000000000318
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