Recent Progress in Superparamagnetic Iron Oxide Nanoparticles

Superparamagnetic iron oxide nanoparticles(SPIONs)have immeasurable potentials in many fields such as nanobiotechnology and biomedical engineering because of their superparamagnetic properties and small particle size.This review introduces the methods for SPIONs synthesis,including co-precipitation,thermal decomposition,microemulsion and hydrothermal reaction,and surface modification of SPIONs with organometallic and inorganic metals,surface modification for targeted drug delivery,and the use of SPIONs as a contrast agent.In addition,this article also provides an overview of recent progress in SPIONs for the treatment of glioma,lung cancer and breast cancer.

Current status of superparamagnetic iron oxide contrast agents for liver magnetic resonance imaging

Five types of superparamagnetic iron oxide （SPIO）,i.e. Ferumoxides （Feridex？ Ⅳ, Berlex Laboratories）,Fe r u c a r b o t ra n （ Re s ov i s t？, B aye r H e a l t h c a re ） ,Ferumoxtran-10 （AMI-227 or Code-7227, Combidex？, AMAG Pharma; Sinerem？, Guerbet）, NC100150（Clariscan？, Nycomed,） and （VSOP C184, Ferropharm）have been designed and clinically tested as magneticresonance contrast agents. However, until nowResovist？ is current available in only a few countries.The other four agents have been stopped for furtherdevelopment or withdrawn from the market. AnotherSPIO agent Ferumoxytol （Feraheme） is approved forthe treatment of iron deficiency in adult chronic kidneydisease patients. Ferumoxytol is comprised of ironoxide particles surrounded by a carbohydrate coat, andit is being explored as a potential imaging approach forevaluating lymph nodes and certain liver tumors.

Biodistribution and Toxicity Assessment of Superparamagnetic Iron Oxide Nanoparticles In Vitro and In Vivo

Biodistribution and toxicity assessment are critical for safe clinical use of newly developed medicines.Superparamagnetic iron oxide nanoparticles (SPION)are effective carriers for targeted drug delivery.This study aimed to examine the toxicity and biodistribution of SPION coated with polyethylenimine (PEI)(SPION-PEI)designed for small interfering RNA (siRNA) delivery both in vitro and in vivo.SPION-PEI/siRNA complexes were prepared at different weight ratios.Cytotoxic effects of SPION-PEI/siRNA on HSC-T6 cell viability were determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT).Rats were divided into three groups:a control group,a normal-saline group and a SPION-PEI/siRNA group.After a single intravenous injection,in vivo nanoparticle biodistribution and accumulation were evaluated by Prussian blue staining in the heart,liver,spleen,lung and kidney 8 h,24 h,and 7 days after the injection.Their distribution was histologically studied at the three time points by measuring ironpositive areas (μm2)in organ sections stained with Prussian blue.The same organs were analyzed by H&E staining for any possible histopathological changes.Furthermore,biochemical indexes such as alanine amino transaminase (ALT),aspartate transaminase (AST),blood urea nitrogen (BUN)and creatinine (CREA)were also assessed at all experimental time points.Electrophoresis exhibited that the SPION-PEI could retard siRNA altogether at weight ratios above 4.MTT assay showed that SPION-PEI loaded with siRNA had low cytotoxicity.In vivo study revealed that the liver and spleen were the major sites of SPION-PEI/siRNA deposition.The iron content was significantly increased in the liver and spleen,peaking 24 h after intravenous injection and then declining gradually.No evidence was found of irreversible histopathological damage to any of the organs tested.These results suggested that most SPION-PEI/siRNA complexes were distributed in the liver and spleen,which might be the target organs of SPION-PEI/siRNA complexes.SPION- PEI/siRNA may serve as in vivo carrier for biomedical medicines.

Toxicity of superparamagnetic iron oxide nanoparticles: Research strategies and implications for nanomedicine

Superparamagnetic iron oxide nanoparticles(SPIONs) are one of the most versatile and safe nanoparticles in a wide variety of biomedical applications. In the past decades, considerable efforts have been made to investigate the potential adverse biological effects and safety issues associated with SPIONs, which is essential for the development of next-generation SPIONs and for continued progress in translational research. In this mini review, we summarize recent developments in toxicity studies on SPIONs, focusing on the relationship between the physicochemical properties of SPIONs and their induced toxic biological responses for a better toxicological understanding of SPIONs.

In Vitro Targeted Magnetic Delivery and Tracking of Superparamagnetic Iron Oxide Particles Labeled Stem Cells for Articular Cartilage Defect Repair

To assess a novel cell manipulation technique of tissue engineering with respect to its ability to augment superparamagnetic iron oxide particles (SPIO) labeled mesenchymal stem cells (MSCs) density at a localized cartilage defect site in an in vitro phantom by applying magnetic force. Meanwhile, non-invasive imaging techniques were use to track SPIO-labeled MSCs by magnetic resonance imaging (MRI). Human bone marrow MSCs were cultured and labeled with SPIO. Fresh degenerated human osteochondral fragments were obtained during total knee arthroplasty and a cartilage defect was created at the center. Then, the osteochondral fragments were attached to the sidewalls of culture flasks filled with phosphate-buffered saline (PBS) to mimic the human joint cavity. The SPIO-labeled MSCs were injected into the culture flasks in the presence of a 0.57 Tesla (T) magnetic force. Before and 90 min after cell targeting, the specimens underwent T2-weighted turbo spin-echo (SET2WI) sequence of 3.0 T MRI. MRI results were compared with histological findings. Macroscopic observation showed that SPIO-labeled MSCs were steered to the target region of cartilage defect. MRI revealed significant changes in signal intensity (P<0.01). HE staining exibited that a great number of MSCs formed a three-dimensional (3D) cell "sheet" structure at the chondral defect site. It was concluded that 0.57 T magnetic force permits spatial delivery of magnetically labeled MSCs to the target region in vitro. High-field MRI can serve as an very sensitive non-invasive technique for the visualization of SPIO-labeled MSCs.

Magnetic labeling of primary murine monocytes using very small superparamagnetic iron oxide nanoparticles

Due to their very small size,nanoparticles can interact with all cells in the central nervous system.One of the most promising nanoparticle subgroups are very small superparamagnetic iron oxide nanoparticles(VSOP)that are citrate coated for electrostatic stabilization.To determine their influence on murine blood-derived monocytes,which easily enter the injured central nervous system,we applied VSOP and carboxydextran-coated superparamagnetic iron oxide nanoparticles(Resovist).We assessed their impact on the viability,cytokine,and chemokine secretion,as well as iron uptake of murine blood-derived monocytes.We found that(1)the monocytes accumulated VSOP and Resovist,(2)this uptake seemed to be nanoparticle-and time-dependent,(3)the decrease of monocytes viability was treatment-related,(4)VSOP and Resovist incubation did not alter cytokine homeostasis,and(5)overall a 6-hour treatment with 0.75 mM VSOP-R1 was probably sufficient to effectively label monocytes for future experiments.Since homeostasis is not altered,it is safe to label blood-derived monocles with VSOP.VSOP labeled monocytes can be used to study injured central nervous system sites further,for example with drug-carrying VSOP.

Distribution of c-erbB2 Antisense Probe Labeled with Superparamagnetic Iron Oxide Nanoparticles in the Major Organs of Mice on MR Imaging

Background: The aim of this study was to investigate the distribution of the c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles in the major organs of mice by MR imaging. Methods: Sixty BALB/c mice were randomly divided into experimental and control groups. MR scans were performed in each mouse of the experimental group at five different time points (10, 30, 60, 180 and 360 min) after injection of the antisense probe. The signal from each major organ (liver, spleen, heart, kidney and muscle tissue) in comparison with the background signal (signal to noise ratio) was determined at each time point as a measure of the distribution of the antisense probe. Six control mice were killed at each of the same time points and the organs immediately removed for determination of their iron content. Results: After injection of the antisense probe, the highest enrichment of the probe was seen in the spleen, reaching a peak at 180 min, followed by the liver, muscle, heart and kidney. Conclusions: MR imaging can visualize the distribution of c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles in the major organs of mice, and this may provide the basis for further in vivo studies of MR imaging time and dose selection.

Hypoxia Enhances the Therapeutic Potential of Superparamagnetic Iron Oxide-labeled Adipose-derived Stem Cells for Myocardial Infarction

Adipose-derived stem cells(ASCs) induce therapeutic angiogenesis due to pro-angiogenic cytokines secretion. Superparamagnetic iron oxide(SPIO) nanoparticles are critical for magnetic resonance(MR) tracking of implanted cells. Hypoxia is a powerful stimulus for angiogenic activity of ASCs. In this study, we investigated whether therapeutic potency could be enhanced by implantation of hypoxia-preconditioned SPIO-labeled ASCs(SPIOASCs) into the infarcted myocardium. ASCs and SPIOASCs were cultured under 2% O_2(hypoxia) or 95% air(normoxia). Cells were intramyocardially injected into the infarcted myocardium after 48-h culture. We found that hypoxia culture increased the m RNA expression of hypoxia-inducible factor-1 alpha(HIF-1α) and vascular endothelial growth factor(VEGF) in ASCs and SPIOASCs. The VEGF protein in the conditioned medium was significantly higher in hypoxic ASCs and SPIOASCs than in normoxic ASCs and SPIOASCs. The capillary density and left ventricular contractile function in the infarcted myocardium were significantly higher 4 weeks after implantation with hypoxic ASCs and SPIOASCs than with normoxic ASCs and SPIOASCs. Improvement in the capillary density and left ventricle function didn't differ between hypoxic ASCs-transplanted rats and hypoxic SPIOASCs-transplanted rats. Hypoxic culture enhanced the angiogenic efficiency of ASCs. It was concluded that implantation of hypoxic ASCs or SPIOASCs promotes therapeutic angiogenesis and cardiac function recovery in the infarcted myocardium. SPIO labeling does not impact the beneficial effect of hypoxic ASCs.

Comparative Study of Images with Pathology:Superparamagnetic Iron Oxide-enhanced Magnetic Resonance Image(MRI)of Splenic VX2 Tumor in Rats

建立一个啮齿类动物的目的怒气的 VX2 肿瘤当模特儿，到在提高的磁性的回声图象(MRI ) 和病理学的变化提高了评估超级顺磁的氧化铁的能力的超级顺磁的氧化铁上的信号紧张的变化之间的分析关系为脾的转移的察觉的 MRI。8 啮齿类动物怒气的 VX2 肿瘤建模的方法成功地被建立。图象在超级顺磁的氧化铁的管理前后被获得。有 450 毫秒的一重复时间(TR ) 的 T1 加权的纺纱回响(SE ) 脉搏顺序，和 12 毫秒(TR/TE=450/12 ) 的回响时间(TE ) 被使用。T2 加权的 SE 脉搏顺序的成像参数如下：TR/TE=4000/128。扫描 T1 加权的脾的 VX2 肿瘤的平凡先生上的结果看低亚硫酸钠紧张或 isointensity 哪个接近了到脾的实质的 SI。因此，所有损害没清楚地被显示。在超级顺磁的氧化铁改进 T2WI 顺序上，脾的实质的 SI 与 55.04% 的信号紧张损失(PSIL ) 的百分比显然减少了，但是肿瘤的 SI 显然没与 0.87% 的 PSIL 被改变。不过，在损害附近的正常脾的实质的 SNR 比较地有明显的差别(P【0.001 ) 。因此，在肿瘤和怒气之间的对比清楚地增加了，并且肿瘤显示了更多。而且在 VX2 肿瘤和脾的实质之间的 contrast-to-noise (CNR ) 在超级顺磁的氧化铁(P【0.001 ) 的 admininstration 前后有明显的差别。T1WI 定序 tumor-to-spleen 的对比的超级顺磁的氧化铁改进上的结论是差的。因此在怒气描绘损害不是敏感的。在超级顺磁的氧化铁上提高了损害的对比度显然增加的 T2WI。因而，超级顺磁的铁扫描的提高氧化物的 T2WI MRI 能为怒气的损害改进察觉和描述的率。

Superparamagnetic Iron Oxide Labeling of Spinal Cord Neural Stem Cells Genetically Modified by Nerve Growth Factor-β

This study established superparamagnetic iron oxide (SPIO)-labeled nerve growth factor-β (NGF-β) gene-modified spinal cord-derived neural stem cells (NSCs). The E14 rat embryonic spinal cord-derived NSCs were isolated and cultured. The cells of the third passage were transfected with plasmid pcDNA3-hNGFβ by using FuGENE HD transfection reagent. The expression of NGF-β was measured by immunocytochemistry and Western blotting. The positive clones were selected, allowed to proliferate and then labeled with SPIO, which was mediated by FuGENE HD transfection reagent. Prussian blue staining and transmission electron microscopy (TEM) were used to identify the SPIO particles in the cells. The distinctive markers for stem cells (nestin), neuron (β-Ⅲ-tubulin), oli-godendrocyte (CNPase) and astrocyte (GFAP) were employed to evaluate the differentiation ability of the labeled cells. The immunocytochemistry and western blotting showed that NGF-β was expressed in spinal cordderived NSCs. Prussian blue staining indicated that numerous blue-stained particles appeared in the cytoplasma of the labeled cells. TEM showed that SPIO particles were found in vacuolar structures of different sizes and the cytoplasma. The immunocytochemistry demonstrated that the labeled cells were nestin-positive. After differentiation, the cells expressed β-III-tubulin, CNPase and GFAP. It was concluded that the SPIO-labeled NGF-β gene-modified spinal cord-derived NSC were successfully established, which are multipotent and capable of self-renewal.

Growth and differentiation of neural stem cells with superparamagnetic iron oxides labeling in vitro

Objective: To study the growth and differentiation of superparamagnetic iron oxides(SPIOs) labeled neural stem cells(NSCs).Methods: After NSCs were cultured and subcultured from newborn rat brain,they were magnetically labeled with ferumoxides(a kind of SPIOs).Growth,differentiation and other biology properties of the cells were investigated with immunocytochemistry,transmission electron microscopy(TEM) and Prussian blue staining.Results: Nestin positive cells were found in the culture and offspring clones.NSCs could be differentiated into positive GFAP and NF200 cells in serum culture.When NSCs incubated with ferumoxides,the iron particles were seen in intracellular as well as in offspring clones.With the increase in concentration of ferumoxides(5.6-11.2 μg/ml),ferumoxides showed no significant difference effects on the growth and differentiation of NSCs.When the concentration of ferumoxides exceeded 22.4 μg/ml,there was significant difference(P<0.05). Conclusion: We successfully label NSCs with ferumoxides,it is useful for tracking of magnetic labeled NSCs in vivo with MRI.

Self-assembled superparamagnetic nanoparticles as MRI contrast agents — A review

Recent progress of the preparation and applications of superparamagnetic iron oxide(SPIO) clusters as magnetic resonance imaging(MRI) probes is reviewed with regard to their applications in labeling and tracking cells in vivo, in diagnosis of cardiovascular diseases and tumors, and in drug delivery systems. Magnetic nanoparticles(NPs), especially SPIO nanoparticles, have long been used as MRI contrast agents and as an advantageous nanoplatform for drug delivery,taking advantage of their unique magnetic properties and ability to function at the molecular and cellular levels. Due to advances in nanotechnology, various means to control SPIO NPs' size, composition, magnetization and relaxivity have been developed, as well as ways to usefully modify their surface. Recently, self-assembly of SPIO NP clusters in particulate carriers — such as polymeric micelles, vesicles, liposomes, and layer-by-layer(Lb L) capsules — have been widely studied for application as ultrasensitive MRI probes, owing to their remarkably high spin–spin(T2) relaxivity and convenience for further functionalization.

磁响应水凝胶在骨组织工程中的作用与优势

背景:磁响应水凝胶在骨组织工程中具有极大的优势,有利于微创、高效地促进成骨。目的:阐述磁响应水凝胶在骨组织工程领域的应用进展。方法:检索PubMed、Web of Science、万方和中国知网数据库检索相关文献,英文检索词为“Magnetic Hydrogels,Magnetic Nanoparticles,Superparamagnetic Nanoparticles,Fe3O4,SPIONs,Magnetic Fields,Bone Regeneration,Bone Repair,Bone Tissue Engineering”;中文检索词为“磁性水凝胶、磁性纳米粒子、超顺磁性氧化铁纳米粒、磁场、氧化铁纳米粒、骨再生、骨重建、骨修复、骨组织工程”,根据纳入与排除标准对所有文章进行初筛后,最终纳入60篇文章进行综述。结果与结论:①近年来由于磁性纳米粒子的出现,大量的磁响应支架材料被开发出来,其中,含有氧化铁纳米粒子和超顺磁性氧化铁纳米粒子的磁响应水凝胶力学性能突出、生物相容性良好,能够快速响应外部磁场,为种子细胞提供成骨所需的磁机械信号。②磁响应水凝胶可以作为载体精准调控生长因子的释放时机。③基于磁响应水凝胶的三维微环境培养平台下,磁响应水凝胶与细胞之间的界面磁力能够激活细胞表面敏感受体、增强细胞活性、促进新生骨质与宿主骨的整合。④可注射磁响应水凝胶能够应用于骨肿瘤的磁热疗以及生物成像领域。⑤目前,磁响应水凝胶有望模拟出天然骨组织中观察到的各向异性分层结构,然而关于磁响应水凝胶的研究大多集中于体外研究,与体内的局部微环境作用机制仍然不充分。⑥因此,目前基于磁性纳米粒子已经成功地应用于磁共振成像的示踪,未来有望在磁性纳米粒子的性能上优化,构建具有合适降解性能、机械性能和血管功能化的能够实时监测体内变化的磁响应水凝胶。

脉冲占空比对磁性微泡介导的聚焦超声温升效应的影响

集合多种诊断和治疗功能的声/磁造影剂微泡的研究与开发已经成为当前医学超声、生物医学工程及临床应用领域共同关注的热点问题.超顺磁氧化铁纳米颗粒具有独特的磁性特征和良好的生物相容性,可被用作核磁共振造影剂来提升影像对比度、空间分辨率及临床诊断准确性.我们的前期工作表明,通过将超顺磁氧化铁纳米颗粒挂载于常规超声造影剂微泡表面,可以成功构建多模态诊断及治疗介质,显著改变超声造影剂微泡的尺度分布及包膜粘弹系数等物理特性,进而影响微泡造影剂的声散射特性及其声空化效应和热效应.然而,此前的研究仅考虑了声场强度和微泡浓度等影响因素,对于脉冲超声时间特性对磁性微泡造影剂动力学响应的影响的相关研究仍有所欠缺.本文通过热电偶对凝胶仿体血管模型中流动的双模态磁性微泡在不同占空比超声脉冲信号作用下,产生温升效应开展了系统的实验测量,并基于有限元模型对实验结果进行了仿真验证.结果显示,脉冲信号占空比的提升是增强血管中磁性微泡在聚焦超声作用下温升效果的关键性时间影响因素.本文的研究成果将有助于更好地理解不同超声作用参数对双模态磁性微泡的热效应的影响机制,对保障双模态磁性微泡在临床热疗应用中的安全性和有效性具有重要的指导意义.

基于频率筛选的磁粒子成像量化分析研究

为实现磁粒子成像(magnetic particle imaging,MPI)中示踪剂铁量化,本研究基于仿真程序,采集二维扫描图像,筛选信号频率并重建图像,以聚类结果作为先验信息,约束水平集函数的演化,对示踪剂图像进行分割,并借助Dice系数、IoU等参数定量评估分割效果。通过计算分割区域的信号强度总和,建立MPI信号与已知示踪剂铁含量的校正曲线。结果显示,频率筛选后显著缩短了信号重建时间;基于先验的水平集方法Dice系数和IoU均大于0.90,实现了肿瘤区域较精准的分割;通过本研究建立的MPI信号强度与铁含量的校正曲线,实现了示踪剂铁量化,平均误差为3.11%,最小误差0.03%。结果表明,基于先验的水平集方法可实现较精确的图像分割和铁量化,为MPI临床前定量研究提供参考。

超顺磁性氧化铁纳米粒子在肿瘤诊断及治疗方面的应用

超顺磁性氧化铁纳米粒子(superparamagnetic iron oxide nanoparticle, SPION)由于其独特的性质,如低毒、生物相容性、强大的磁性,以及在多功能模式中的优越作用,在肿瘤诊断、构建多模态肿瘤分子影像探针及治疗方面展现出巨大的潜力,今后可以在临床上提高肿瘤诊断的特异性、敏感性,实现诊疗一体化,本文从SPION的成像机制、合成方法出发,阐述近年来SPION在肿瘤的各种靶向成像、多模态成像和治疗方面的研究进展,展望未来SPION在肿瘤诊断及治疗中的发展前景,旨在为更好地构建基于SPION的新型诊疗一体化肿瘤探针提供参考。

Superparamagnetic iron oxide nanoparticle targeting of adipose tissue-derived stem cells in diabetes-associated erectile dysfunction

可勃起的机能障碍(编辑) 是糖尿病的主要复杂并发症，并且有编辑的许多糖尿病的人对普通编辑治疗倔强。脂肪质的导出织物的干细胞(ADSC ) 被显示了在糖尿病的动物模型改进可勃起的功能。然而，到损坏地点的不适当的房间 homing 限制了他们的功效。因此，我们探索了在与一个外部磁场改进导致 streptozotocin 的糖尿病的老鼠的可勃起的功能上用 superparamagnetic 氧化铁 nanoparticles (SPION ) 标记的 ADSC 的效果。我们发现那 SPION 有效地合并了到 ADSC 并且没在干细胞性质上施加任何否定效果。ADSC 的磁性的指向在阴茎海绵体贡献了长期的细胞保留并且独自与 ADSC 注射相比改进了糖尿病的老鼠的可勃起的功能。另外， ADSC 的 paracrine 效果看起来在功能、结构的恢复起主要作用。因此，磁性的指导地的 ADSC 治疗是为联系糖尿病的编辑治疗的一条有效途径。

Synthesis and application of superparamagnetic iron oxide nanoparticles in targeted therapy and imaging of cancer

Superparamagnetic iron oxide(SPIO)nanoparticles have become a popular strategy of cancer treatment and molecular imaging because of their versatile properties and biocompatibility.A variety of studies have shown the exciting potential of functionalized SPIO nanoparticles,such as surface-coated,targeted ligandconjugated,and/or drug-loaded SPIO nanoparticles,as powerful tools for targeted imaging and therapy.Moreover,the applications of SPIO nanoparticles that integrate diagnosis and therapy in SPIO nanoparticles facilitate the monitoring of therapeutic efficacy during treatment.In the present review,we primarily concentrate on the recent advancements in the field of SPIO nanoparticles in terms of synthesis,targeted therapy,and cancer imaging.