Ferritin surplus in mouse spleen 14 months after intravenous injection of iron oxide nanoparticles at clinical dose

In this study,we followed the biodegradation of ultra-small superparamagnetic iron oxide nanoparticles injected intravenously at clinical doses in mice.An advanced fitting procedure for magnetic susceptibility curves and lowtemperature hysteresis loops was used to fully characterize the magnetic size distribution as well as the magnetic anisotropy energy of the injected P904 nanoparticles (Guerbet Laboratory).Additional magnetometry measurements and transmission electronic microscopy observations were systematically performed to examine dehydrated samples from the spleen and liver of healthy C57B16 mice after nanoparticle injection,with sacrifice of the mice for up to 14 months.At 3 months after injection,the magnetic properties of the spleen and liver were dramatically different.While the liver showed no magnetic signals other than those also present in the reference species,the spleen showed an increased magnetic signal attributed to ferritin.This surplus of ferritin remained constant up to 14 months after injection.     

非水介质中制备纳米氧化铁

在严格无水的条件下,制备了氧化铁纳米粒子,采用FTIR、XRD、TEM、TG-DTA、Mossbauer谱等方法对所得的纳米粒子进行了表征和分析.实验结果证明:室温晾干后,得到无定形的FeOOH超细粉体;通过控制热处理的温度;可以得到不同晶型的氧化铁纳米粒子.即:在300℃热处理1h,主要得到约30nm的Fe_3-xO₄,450℃处理1h,可得到粒径约为98nnm的α-Fe₂O₃粒子.     

Preparation and Application of Amino- and Dextran-Modified Superparamagnetic Iron Oxide Nanoparticles

Amino-dextran-functionalized superparamagnetic iron oxide nanoparticles (SPION) were synthesized by two-steps: Dextran-modified SPION was obtained by “one-step” co-precipitation method. Then, N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAPS) was added to the resultant dextran-SPION to prepare amino-dextran-functionalized SPION (AEAPS/Dex-SPION). The particles were characterized by vibrating sample magnetometer (VSM), transmission electron micrographs (TEM), atomic force micrographs (AFM), gas chromatography and atomic absorption spectrophotometry. The size of the modified particles varied in a range of 30 to 40 nm and did not change significantly after modification. The binding rate of AEAPS was 91.15%. A monoclonal antibody against S100 (anti-S-100), a gold standard for the diagnosis of melanocytic lesions, was conjugated to the AEAPS/Dex-SPION to prepare immuno-SPION. From the result in melanoma B16 cell, the immuno-SPION was proven to have a bio-targeting activity. Such AEAPS/Dex-SPION might be very useful for bio-magnetically targeted detection in early melanocytic lesions.     

Plasma Proteome Association and Catalytic Activity of Stealth Polymer‐Grafted Iron Oxide Nanoparticles

Polyethylene glycol (PEG) is widely used as an antifouling and stealth polymer in surface engineering and nanomedicine. However, recent research has revealed adverse effects of bioaccumulation and immunogenicity following the administration of PEG, prompting this proteomic examination of the plasma protein coronae association with superparamagnetic iron oxide nanoparticles (IONPs) grafted with brushed PEG (bPEG) and an alternative, brushed phosphorylcholine (bPC). Using label‐free quantitation by liquid chromatography tandem‐mass spectrometry, this study determines protein abundances for the in vitro hard coronae of bare, bPC‐, and bPEG‐grafted IONPs in human plasma. This study also shows unique protein compositions in the plasma coronae of each IONP, including enrichment of coagulation factors and immunogenic complement proteins with bPEG, and enhanced binding of apolipoproteins with bPC. Functional analysis reveals that plasma protein coronae elevate the horseradish peroxidase‐like activities of the bPC‐ and bPEG‐IONPs by approximately twofold, an effect likely mediated by the diverse composition and physicochemical properties of the polymers as well as their associated plasma proteins. Taken together, these observations support the rational design of stealth polymers based on a quantitative understanding of the interplay between IONPs and the plasma proteome, and should prove beneficial for the development of materials for nanomedicine, biosensing, and catalysis.     

New Insights into Biocompatible Iron Oxide Nanoparticles: A Potential Booster of Gene Delivery to Stem Cells

Gene delivery to stem cells is a critical issue of stem cells‐based therapies, still facing ongoing challenges regarding efficiency and safety. Recent advances in the controlled synthesis of biocompatible magnetic iron oxide nanoparticles (IONPs) have provided a powerful nanotool for assisting gene delivery to stem cells. However, this field is still at an early stage, with well‐designed and scalable IONPs synthesis highly desired. Furthermore, the potential risks or bioeffects of IONPs on stem cells are not completely figured out. Therefore, in this review, the updated researches focused on the gene delivery to stem cells using various designed IONPs are highlighted. Additionally, the impacts of the physicochemical properties of IONPs, as well as the magnetofection systems on the gene delivery performance and biocompatibility are summarized. Finally, challenges attributed to the potential impacts of IONPs on the biologic behaviors of stem cells and the large‐scale productions of uniform IONPs are emphasized. The principles and challenges summarized in this review provide a general guidance for the rational design of IONPs‐assisted gene delivery to stem cells.     

Anti-Platelet Effect Induced by Iron Oxide Nanoparticles: Correlation with Conformational Change in Fibrinogen

Iron oxide nanoparticles are developed for various biomedical applications, however, there is limited understanding regarding their effects and toxicity on blood components. The particles traveling in circulation inevitably interact with blood cells and plasma proteins and may interfere with hemostasis. Specifically, this study focuses on the influence of superparamagnetic iron oxide nanoparticles (SPIONs) coated with a biocompatible polymer, polyvinyl alcohol (PVA), on platelet function. Here, engineered SPIONs that are functionalized with various PVA coatings to provide these particles with different surface charges and polymer packing are described. These formulations are assessed for any interference with human platelet functions and coagulation, ex vivo. Positively charged SPIONs induce a significant change in platelet GPIIb-IIIa conformation, indicative of platelet activation at the dose of 500 µg mL⁻¹. Remarkably, engineered PVA(polyvinyl alcohol)-SPIONs all display a robust dose-dependent anti-platelet effect on platelet aggregation, regardless of the PVA charge and molecular weight. After assessing hypotheses involving SPION-induced steric hindrance in platelet–platelet bridging, as well as protein corona involvement in the antiplatelet effect, the study concludes that the presence of PVA-SPIONs induces fibrinogen conformational change, which correlates with the observed dose-dependent anti-platelet effect.     

磁性氧化铁高效磁共振造影剂的制备及应用

采用高温热分解法, 以乙酰丙酮铁为铁源, 生物相容性良好的聚乙二醇(PEG1000)作为溶剂、还原剂及修饰剂制备PEG修饰的氧化铁纳米粒子(PEG-SPIONs), 并研究其在小鼠体内的造影效果。X射线衍射(XRD)分析表明样品中含有Fe₃O₄晶相。透射电镜(TEM)结果显示, 合成的PEG-SPIONs形貌均一, 主要为等轴晶形, 纳米粒度及电位分析表明其表面呈负电性, 分散在水中的动力学粒径为20 nm。磁性能结果表明合成的PEG-SPIONs室温下具有超顺磁性, 并且具有较高的r₂/r₁值。细胞活性研究表明PEG-SPIONs具有较低的生物毒性, 体内的磁共振成像结果显示出PEG-SPIONs优异的对比增强效果, 说明PEG-SPIONs可以作为高效的T₂磁共振成像造影剂。     

Tolerogenic Iron Oxide Nanoparticles in Type 1 Diabetes: Biodistribution and Pharmacokinetics Studies in Nonobese Diabetic Mice

Nanoparticle (NP) administration is among the most attractive approaches to exploit the synergy of different copackaged molecules for the same target. In this work, iron oxide NPs are surface‐engineered for the copackaging of the autoantigen proinsulin, a major target of adaptive immunity in type 1 diabetes (T1D), and 2‐(1′H‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylic acid methylester (ITE), a small drug conditioning a tolerogenic environment. Magnetic resonance imaging (MRI) combined with magnetic quantification are used to investigate NP biokinetics in nonobese diabetic (NOD) mice and control mice in different organs. Different NP biodistribution, with in particular enhanced kidney elimination and a stronger accumulation in the pancreas for prediabetic NOD mice, is observed. This is related to preferential NP accumulation in the pancreatic inflammatory zone and to enhancement of renal elimination by diabetic nephropathy. For both mouse strains, an MRI T2 contrast enhancement at 72 h in the liver, pancreas, and kidneys, and indicating recirculating NPs, is also found. This unexpected result is confirmed by magnetic quantification at different time points as well as by histological evaluation. Besides, such NPs are potential MRI contrast agents for early diagnosis of T1D.     

MPEG修饰的纳米氧化铁粒子的合成及清洗工艺

以MPEG为溶剂、还原剂及修饰剂,Fe(acac)3为铁源,通过高温热分解法制备了超顺磁性氧化铁纳米粒子(SPIONs).采用饱和食盐水清洗方法对合成的粒子进行收集,经透析除去其表面残留的NaCl.采用XRD,TEM,HRTEM,SQUID,ICP MS,TGA,FT IR,纳米粒度与Zeta电位分析仪对样品进行表征.结果表明:经透析处理后氧化铁的质量分数为NaCl的6.9×104倍,制备的SPIONs具有高的结晶度及单分散性,在300K下,具有超顺磁性,饱和磁化强度为53.7A· m2·kg-1;具有惰性端基的MPEG修饰于SPIONs表面,为其提供了良好的水分散性.采用盐桥法萃取清洗工艺可清除过量的MPEG,有利于SPIONs更好的应用在生物医学领域.     

用原子力显微镜研究葡聚糖包覆纳米氧化铁微粒的形貌特征

采用化学共沉淀法合成了葡聚糖包覆的超顺磁纳米氧化铁微粒,用原子力显微镜对其分布状态、微粒形貌和尺度等进行了表征,并与透射电镜观察结果进行了比较。结果表明：葡聚糖包覆的超顺磁纳米氧化铁微粒大小均匀且有规律的定向分布,无团聚现象;透射电镜显示其核心氧化铁纳米粒子的外形主要为不规则的球形,粒径5～20nm被葡聚糖包覆后的纳米氧化铁微粒呈长方体,尺寸为（200-300）nm×（400-600）nm×（50-70）nm。     

A Surface‐Charge Study on Cellular‐Uptake Behavior of F3‐Peptide‐Conjugated Iron Oxide Nanoparticles

Surface‐charge measurements of mammalian cells in terms of Zeta potential are demonstrated as a useful biological characteristic in identifying cellular interactions with specific nanomaterials. A theoretical model of the changes in Zeta potential of cells after incubation with nanoparticles is established to predict the possible patterns of Zeta‐potential change to reveal the binding and internalization effects. The experimental results show a distinct pattern of Zeta‐potential change that allows the discrimination of human normal breast epithelial cells (MCF‐10A) from human cancer breast epithelial cells (MCF‐7) when the cells are incubated with dextran coated iron oxide nanoparticles that contain tumor‐homing F3 peptides, where the tumor‐homing F3 peptide specifically bound to nucleolin receptors that are overexpressed in cancer breast cells.     

Amino‐polyvinyl Alcohol Coated Superparamagnetic Iron Oxide Nanoparticles are Suitable for Monitoring of Human Mesenchymal Stromal Cells In Vivo

Mesenchymal stromal cells (MSCs) are promising candidates in regenerative cell‐therapies. However, optimizing their number and route of delivery remains a critical issue, which can be addressed by monitoring the MSCs’ bio‐distribution in vivo using super‐paramagnetic iron‐oxide nanoparticles (SPIONs). In this study, amino‐polyvinyl alcohol coated (A‐PVA) SPIONs are introduced for cell‐labeling and visualization by magnetic resonance imaging (MRI) of human MSCs. Size and surface charge of A‐PVA‐SPIONs differ depending on their solvent. Under MSC‐labeling conditions, A‐PVA‐SPIONs have a hydrodynamic diameter of 42 ± 2 nm and a negative Zeta potential of 25 ± 5 mV, which enable efficient internalization by MSCs without the need to use transfection agents. Transmission X‐ray microscopy localizes A‐PVA‐SPIONs in intracellular vesicles and as cytosolic single particles. After identifying non‐interfering cell‐assays and determining the delivered and cellular dose, in addition to the administered dose, A‐PVA‐SPIONs are found to be non‐toxic to MSCs and non‐destructive towards their multi‐lineage differentiation potential. Surprisingly, MSC migration is increased. In MRI, A‐PVA‐SPION‐labeled MSCs are successfully visualized in vitro and in vivo. In conclusion, A‐PVA‐SPIONs have no unfavorable influences on MSCs, although it becomes evident how sensitive their functional behavior is towards SPION‐labeling. And A‐PVA‐SPIONs allow MSC‐monitoring in vivo.     

一种铁纳米材料的制备方法

在常温常压、无任何催化剂的条件下,用电子束辐照法制备纳米铁的前驱体纳米氧化铁,然后用高纯氢还原纳米氧化铁可制得纳米铁.采用X射线衍射仪(XRD)分析试验产物的结构、大小,并用激光衍射粒度分布仪(LSPSDA)观测其粒度分布,可以验证实验效果.介绍了用电子束辐照技术结合高纯氢还原的方法制备铁纳米材料,并探讨了水溶液铁离子的辐射化学反应机理,以及影响纳米氧化铁还原的主要因素.