摘要
背景与目的
分子成像是一个迅速崛起的生物医学研究手段和临床学科,其目标是无创,定量可视化发生在细胞和亚细胞水平的体内分子过程。一般来说,分子成像的应用要求快速、敏感、高分辨率力的影像技术,结合使用对比剂从而使细胞和亚细胞水平生物过程能够可视化。至目前为止,单光子发射计算机断层扫描(SPECT),正电子发射计算机断层扫描(PET)和光学成像(Optical imaging)技术仍然是体内临床前分子影像最常用的影像方法,其主要原因是这些方法高的敏感性。然而核成像技术(PET/SPECT)使用电离辐射,没有提供解剖信息且空间分辨率力低,而光学成像空间分辨力低且深度穿透力受限。因此,近年来磁共振(MR)被引入作为替代方法,由于这个技术提供极好的内在高空间分辨力的软组织对比和无电离辐射。此外,该技术能够在单次试验通过结合不同的成像系列提供解剖信息和弥散,灌注和血流等生理参数。MR已经成为分子影像的一个重要工具,然而MRI的缺点是对于MR造影剂的低敏感性,因此采用不同策略提高造影剂的效力,如研发新颖的纳米颗粒将使MR成像更有利于适合分子影像。
应用MRI结合铁氧颗粒(IONP)为基础的细胞标记技术提供一个良好解决在宿主器官内非侵袭性追踪移植细胞的方法,但这个技术的主要挑战是诱导充足数量的颗粒进入细胞内以弥补细胞分裂所引起的稀释效应,而不影响正常细胞功能。对于细胞标记,尽管SPIO颗粒很容易被巨噬细胞吞噬进入细胞内,然非吞噬细胞及分裂慢的细胞铁氧磁性纳米颗粒吸入却很少,因此有效的细胞标记需要高浓度的纳米颗粒,但这经常引起细胞毒性。当前,提高对比剂内化的一些方法已经提出并进行了研究,最常用方法是利用商业化Feridex结合转染试剂,然而,其缺少通用的公式,试验冗长和单细胞系要获得最优化转染效果易发生错误。
鉴于上述因素,本研究应用MR及新颖高磁矩的磁共振分子成像对比剂-人血清白蛋白-多巴胺-四氧化三铁氧纳米颗粒(Human serum albumin-Dopamine-Fe3O4 Nanoparticles, HSA-IONPs)进行分子影像学研究,通过与商业应用的Feridex纳米颗粒对比研究,研究HSA-IONPs磁特性,各种不同细胞系HSA-IONPs(终浓度为20μg·ml-1铁)细胞标记的有效性,并在不同动物模型中应用HSA-IONPs标记神经干细胞、巨噬细胞行MR分子成像。
目的合成HSA-Dopamine-Fe3O4纳米颗粒(HSA-IONPs)-新颖的磁共振分子成像对比剂并研究其磁特性。
方法油酸涂层铁氧颗粒(15nm)来自Ocean NanoTech公司。对于表面修饰,大约50mg油酸涂层铁氧颗粒分散在5ml氯仿内,20mg多巴胺溶解在2ml DMSO内并加入上述油酸涂层铁氧颗粒的氯仿内,形成一均质溶液,混和溶液加热至70℃后一小时,凉至室温。已烷作为不良溶剂用于沉淀纳米颗粒,15000g离心15min收集纳米颗粒后,用氮气吹干,在超声波的作用下重新分散纳米颗粒进入DMSO。另外,把20mg HSA(人血清白蛋白)溶解在硼酸盐缓冲剂(50nM,PH8.5),在超声作用下,把溶解在DMSO的纳米颗粒滴加至HSA溶液内。合成产物在PBS(PH 7.4)溶液中透析(MWCO 12000-14000)24h以便交换缓冲液并除去游离的多巴胺,此后,得到的纳米颗粒再次离心,30000g离心20min以去除游离的HSA,产物重分散于PBS缓冲液内,小部分聚集物通过注射过滤器(0.22μm)移除。采用电感耦合等离子体发射光谱仪(ICP-AMS)、透射电子显微镜(TEM)、动态光散射(DLS)、Zeta电位及MRI对纳米颗粒进行定量和特征,尾静脉注射Feridex和HSA-Dopamine-Fe3O4纳米颗粒(lOmg Fe/kg)进入正常裸鼠体内后,在不同时间点行肝脏MR T2W成像。
结果DLS测量分散状态的HSA-IONPs流体动力学结果是28.4nm,TEM显示合成的纳米颗粒呈单分散单晶体和圆形结构,无团块聚集现象。Zeta电位结果显示HSA-Dopamine-Fe3O4纳米颗粒呈负电荷(-9.46±1.86MV)。MR Phantom结果显示HSA-IONPs的R2值(R2值=314.5mM-1S-1)明显高于常规应用的Feridex纳米颗粒(Feridex R2值=123.6mM-1S-1),HSA-IONPs显示更好的T2对比,HSA-IONPs可应用于肝脏成像。
结论HSA-Dopamine-Fe3O4纳米颗粒具有更高的磁矩,优于商业应用的铁氧颗粒(Feridex)。
目的研究新型的磁共振分子成像对比剂HSA-IONPs细胞标记的有效性。
方法在不同时间点应用HSA-IONPs和Feridex (20μg Fe-ml-1)纳米颗粒孵育人前列腺癌PC3细胞、人头颈磷状细胞癌UMSCC-22B细胞、神经干细胞、间充质细胞、人胚胎干细胞、巨噬细胞。行普鲁氏蓝染色,核固红反染。MTT分析用于评估纳米颗粒的毒性作用。神经干细胞和巨噬细胞吞噬的纳米颗粒应用ICP-AMS、TEM及MR Phantom成像进行定量和特征。双侧大脑基底节立体定向注射纳米颗粒标记的神经干细胞(1×104)后6h,行MR T2W扫描;建立MCAO脑中风模型,静脉注射巨噬细胞后在不同时间点(扫描前、4h、1d、2d、5d、7d)行MR扫描。
结果低浓度20μg/ml HSA-IONPs即可有效孵育细胞,且不需要转染试剂。TEM见纳米颗粒位于细胞内的内涵体/溶酶体内,纳米颗粒有聚集改变。HSA-IONPs对研究细胞系的生长和分裂没有显著性毒性影响(P<0.05)。与Feridex组相比,ICP-AMS结果显示神经干细胞和巨噬细胞HSA-IONPs组呈现更高的纳米颗粒吸收。HSA-IONPs或Feridex加转染试剂(50μg Fe·ml-1+Lipofactamine 2000)孵育神经干细胞24h,与Feridex相比纳米颗粒吸收有显著性差异。神经干细胞纳米颗粒的孵育浓度与细胞吸收的铁量呈相关依赖性。MR细胞Phantom成像显示T2WI信号强度有显著性差异,未饱和前,R2值与细胞数量呈良好的线性相关关系。体内MR及病理证实HSA-IONPs孵育的神经干细胞比Feridex孵育吸收更多的铁量。MR扫描可用来追踪局灶性脑缺血中风后标记的巨噬细胞迁移。
结论HSA-Dopamine-Fe3O4细胞标记有效且优于Feridex。
目的探讨肿瘤相关巨噬细胞(TAMs) MR成像可行性。
方法应用HSA-IONPs(20μg/ml Fe)孵育巨噬细胞(RAW264.7)24h,经尾静脉注射5×106标记巨噬细胞至皮下4T1荷瘤BALB/c小鼠和22B荷瘤裸鼠,在不同时间点(扫描前、注射后6h、1、2、3或7d),采用7.0 T MR扫描仪行T2W横、冠状位扫描,动物处死后肿瘤及脏器行病理检查。
结果普鲁士蓝染色、电镜及细胞Phantom成像证实细胞标记有效。注射后6h4T1肿瘤坏死囊变中心周围见明显低信号影,24h见坏死区与肿瘤实质区交界部位有不规则环形低信号影;22B肿瘤注射后6h MRI见多发散在灶性低信号影,24h点片状低信号影缩小;两种肿瘤注射后2、3或7d MRI形态、位置和24h相似,但信号强度递减,病理证实标记的巨噬细胞存在,与影像结果一致。
结论TAMs MR成像可行。注射后24h T2WI是显示肿瘤巨噬细胞迁移、浸润肿瘤内的最佳时机,注射后6h可能反映病变局部血流灌注及新生血管的状态,不同的肿瘤之间巨噬细胞分布方式有差异。
Background and purpose
Molecular imaging is a rapidly growing biomedical research tool and clinical discipline aimed at noninvasive,quantitative visualization of in vivo molecular processes occurring at cellular and subcellular levels.In general, molecular imaging applications require fast, sensitive and high-resolution imaging techniques, combined with the use of contrast agents that enable the visualization of biological processes at the cellular and molecular level.Until recently, positron emission tomography (PET), single photon emission computed tomography (SPECT) and optical imaging techniques were the most frequently used imaging modalities for pre-clinical molecular imaging in vivo. This is predominantly attributed to the high sensitivity of these modalities,
However, nuclear imaging techniques (PET/SPECT) use ionizing radiation, provide no anatomical information and have a low spatial resolution. And Optical imaging suffers from limited depth penetration and relatively low spatial resolution.Therefore,magnetic resonance imaging (MRI) has been recently introduced as an alternative, as this technique provides excellent intrinsic soft-tissue contrast at a high spatial resolution without using ionizing radiation. Moreover, this technology has the advantage that both anatomical information and physiological parameters, like diffusion, perfusion and flow, can be obtained within one single experiment by combining different imaging sequences.MR has become an important tool for molecular imaging.The drawback of MRI is however its low sensitivity for MR contrast agents. Nevertheless, different strategies can be applied to improve the efficiency of such agents, and thus make MRI suitable for molecular imaging purposes.
The application of magnetic resonance imaging in conjunction with iron oxide nanoparticle (IONP) based cell labeling techniques, has provided an excellent solutionto the non-invasive tracking of the implanted cells in the host organism. One major challenge for this technique, however, is to induce sufficient amount of particles into the cells to compensate the dilution effect caused by cell division, while not affecting the normal cellular functions. For cell labeling, although SPIO particles are easily internalized by macrophages, uptake by nqnphagocytic and slow-dividing cells is poor, so that high concentrations which often cause cell toxicity are needed for efficient cell labeling.Currently, Several approaches have been raised and investigated to improve the internalization of the contrast agent, with the mostly utilized one being the employment of commercial Feridex in combination with transfection agents. However, lacking of a universal formula, tedious trials and errors have to be made with individual cell line to achieve optimal transfection.
In view of these factors, In the study, we conducted the study of molecular imaging with MR imaging and a novel magnetic resonance contrast agent with high magnetic moment-HSA-Dopamine-Fe3O4 nanoparticles (HSA-IONPs) for. through comparative study of Feridex and HSA-Dopamine-Fe3O4 nanoparticles, we investigaed magnetic properties of HSA-IONPs and cell labeling efficiency for different types of cell lines (final concentration of 20μg·ml-1 Fe), and performed molecular magnetic resonance Imaging using neural stem cells,macrophages labled with HSA-IONPs in different animal models.
Purpose To synthesize HSA-Dopamine-Fe3O4 nanoparticles (HSA-IONPs)-a novel magnetic resonance contrast agent for molecular imaging and study its magnetic properties.
Methods Olecate coated iron oxide nanoparticles (15 nm) were obtained from Ocean NanoTech (Springdale, AR). For surface modification, about 50 mg of oleate coated nanoparticles were dispersed in 5 ml of chloroform. Into the solution,20 mg of dopamine in 2 ml DMSO was added, forming a homogeneous solution. The mixture was heated at 70℃for 1 hour, and was then cooled down to r.t. Hexanes was added as poor solvent to precipitate the nanoparticles, and the nanoparticles were collected by centrifuging at 15,000 g for 15 minutes. Afterwards, they were blow dried with nitrogen, and were redispersed in DMSO with the aid of sonication. On the other hand,20 mg of HSA was dissolved in borate buffer (50 nM, pH 8.5). And with sonication, the nanoparticles in DMSO were dropwise added to the HSA solution. get rid of free dopamine and free HSA.then,were redipersed in PBS buffer. Nanoparticle were quantified and characterized by ICP-AMS、TEM、DSL(dynamic light scattering) and MRI. After normal nude mice were injected with Feridex and HSA-IONPs (10mg Fe/kg) via tail vein.T2W MR scan were performed for studying liver imaging in vivo at different time points.
Results Dynamic light scattering (DLS) measured the hydrodynamic diameter of the HSA-IONPs in their dispersion state, The measurement results in water were 28.4 nm. TEM images showed Nanoparticles were monodisperse and single crystalline with circular structure, no aggregated clumps. The results of zeta potential measurements revealed that the HSA-Dopamine-Fe3O4 nanoparticles exhibited negative zeta potential (-9.46±1.86MV).MR phantom results indicated that R2 value of HSA-IONPs(R2=314.5mM-1S-1) was significent higher than that of the conventiona-lly utilized Feridex nanoparticles (R2=123.6mM-1S-1), those HSA-Dopamine-Fe3O4 show better T2 contrast and can be used for liver imaging.
Conclusion HSA-IONPs have higher magnetic moment and are better than commercial SPIO nanoparticles(Feridex).
Purpose To study cell labeling efficiency of HSA-IONPs as a novel magnetic resonance contrast agent for molecular imaging. Methods HSAIO-NPs or Feridex(final concentration of 20μg·ml-1 Fe) was used to label human prostate cancer PC-3 cells、human head and neck squamous cell carcinoma UMSCC-22B cells、neural stem cells、mesenchymal stem cells、human embryonic stem cells and macrophages respectively at different time points (2、9、12、24h or 48h), All Cells were stained by prussian blue and then counterstained with nuclear fast red. MTT assay was used to evaluate the in vitro cytotoxic effects of nanoparticles. Both nanoparticles phagocytosed by neural stem cells and macrophages were quantified and characterized by ICP-AMS、TEM、and MR Phantom imaging.T2W MR scans were performed 6h after labeled neural stem cells were implanted into bilateral basal ganglia of nude mouse brains by stereotactic injection.24h after the onset of MCAO, macrophages labeled by HSA-IONPs were injected into rats via tail vein and MR scan were performed at different time points (prescan,4h, 1d,2d,5d,7d).
Results All cells were incubated with merely 20μgml particles without transfection agent for efficient cell labeling.TEM analysis results found populations of nanoparticles within endosomes/lysosoms and some aggregation could be seen. no toxicity and no harm on cell growth and division was found for the studied cell lines (P<0.05).The results of ICP-AMS assay showed that neural stem cells and macrophages labeled with HSA-IONPs presented higher uptake of nanoparticles than those labled with Feridex. Neural stem cells were incubated with HSA-IONPs or Feridex plus transfection reagents(50μg Fe·ml-1 plus Lipofactamine 2000) for 24h. Compared with Feridex nanoparticles, neural stem cells labeled with HSA-IONPs and transfection agents presented higher uptake of nanoparticles. There was strong dependence on the concentration of nano-particles and iron uptake of neural stem cells. MR Phantom images showed a significant difference between T2WI signal intensity of cell labled with HSA-IONPs and feridex. There was strong linear correlation between R2 values and number of cells before the saturation limit.In vivo MR imaging and pathological examinations confirmed neural stem cells incubated with HSA-IONPs absored more iron than those incubated with Feridex. MR scans could be used to track macrophage migration after focal cerebral ischemic stroke.
Conclusion Cell labeling efficiency of HSA-IONPs has an advantage over those of Feridex nanoparticle.
Purpose To explore the feasibility of MR imaging for tumor-associated macrophages.
Methods Macrophages(RAW264.7)were incubated with HSA-IONPs (20μg/ml Fe)for 24 hours,Then,5×106 labeled macrophages were injected into subcutaneous 4T1 tumor-bearing BALB/c mice and 22B tumor-bearing nude mice via tail vein. At different time points(0h、6h、1d、2d、3d or 7d), all animals performed transverse and coronal T2-weighted MR scans using a 7.0-T MR imaging unit..After sacrifice at different time points, Tumor、liver、spleen and other organs were removed and processed for histological examination.
Results Prussian blue staining、TEM and cell phantom imaging confirm efficient cell labeling. in 4T1 tumor model,MR images showed significant low signal intensity on T2-weighted imaging surrounding the center of necrosis and cystic degeneration 6 hours after macrophage injection.,irregular ring low signal enhancement could be seen at the junction of necrotic and parenchyma area at 24 hours. In 22B tumor model,MR images presented distinct multiple small scattered foci of low signal intensity on T2-weighted imaging around the center of necrosis and cystic degeneration 6 hours after macrophage injection. at 24 hours, reduced multiple small scattered foci of low signal intensity could be observed.2、3 or 7days after macrophage injection, MR morphology and location of low signal intensity was similar to those at 24 hours after injection on T2-weighted imaging.But, signal intensity gradually dereased over time.pathological examination verified the presence of labeled macrophages, pathological findings were consistent with imaging results.
Conclusion MR imaging for tumor-associated macrophages is feasible.24 hours after macrophage injection is the optimal time point for studing macrophage migrating and infiltrating into tumor on T2-weighted imaging. MR images may indicate the perfusion of local blood flow and the status of neovascularization 6 hours after macrophage injection, The pattern of TAM distribution differed between different tumors.
引文
[1]Weissleder R,Mahmood U. Molecular imaging. Radiology,2001;219(2):316-333.
[2]Strijkers GJ, Mulder WJ, van Tilborg GA, et al. MRI contrast agents:current status and future perspectives, Anticancer Agents Med Chem,2007;7(3):291-305.
[3]Josephs D, Spicer J, O'Doherty M. Molecular imaging in clinical trials. Target Oncol,2009;21. [Epub ahead of print]
[4]Henning TD, Boddington S, Daldrup-Link HE. Labeling hESCs and hMSCs with iron oxide nanoparticles for non-invasive in vivo tracking with MR imaging. J Vis Exp,2008; 31(13):pii: 685.
[5]Mailander V, Lorenz MR, Holzapfel V, et al.Carboxylated superparamagnetic iron oxide particles label cells intracellularly without transfection agents. Mol Imaging Biol,2008; 10(3): 138-46.
[6]Ourednik J, Ourednik V, Lynch WP, et al. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol,2002;20(11):1103-1110.
[7]Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders.Nature,2006; 441(7097):1094-6.
[8]Aranguren XL, McCue JD, Hendrickx B, et al. Multipotent adult progenitor cells sustain function of ischemic limbs in mice. J Clin Invest,2008;118(2):505-14.
[9]Arias-Carrion O, Drucker-Colin R. Neurogenesis as a therapeutic strategy to regenerate central nervous system. Rev Neurol,2007;45(12):739-45.
[10]McCall MD, Toso C, Baetge EE, et al.Are stem cells a cure for diabetes? Clin Sci (Lond), 2009;118(2):87-97.
[11]Kim SU, de Vellis J. Stem cell-based cell therapy in neurological diseases:a review. J Neurosci Res,2009;87(10):2183-200.
[12]Kraitchman DL, Bulte JW. Imaging of stem cells using MRI. Basic Res Cardiol,2008; 103(2):105-13
[13]Wu YL, Ye Q, Foley LM, et al. In situ labeling of immune cells with iron oxide particles:an approach to detect organ rejection by cellular MRI. Proc Natl Acad Sci U S A,2006,103 (6):1852-7.
[14]de Vries IJ, Lesterhuis WJ, Barentsz JO,et al.Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy.Nat Biotechnol,2005;23(11):1407-13.
[15]Shapiro EM, Skrtic S, Koretsky AP. Sizing it up:cellular MRI using micronsized iron oxide particles.Magn Reson Med,2005;53(2):329-38.
[16]Cantillon-Murphy P, Wald LL, Zahn M, et al.Measuring SPIO and Gd contrast agent magnetization using 3 T MRI. NMR Biomed,2009;22(8):891-7.
[17]Kraitchman DL, Heldman AW, Atalar E, et al.In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation,2003; 107(18):2290-2293.
[18]Frank JA, Zywicke H, Jordan EK, et al.Magnetic intracellular labeling of mammalian cells by combining (FDA-approved) superparamagnetic iron oxide MR contrast agents and commonly used transfection agents. Acad Radiol,2002;9(S2):484-487.
[19]Smirnov P. Cellular magnetic resonance imaging using superparamagnetic anionic iron oxide nanoparticles:applications to in vivo trafficking of lymphocytes and cell-based anticancer therapy. Methods Mol Biol,2009;512:333-53.
[20]Long CM, Bulte JW. In vivo tracking of cellular therapeutics using magnetic resonance imaging. Expert Opin Biol Ther,2009;9(3):293-306.
[21]Arbab AS, Frank JA. Cellular MRI and its role in stem cell therapy. Regen Med,2008; 3(2):199-215.
[22]Duda J, Karimi M, Negrin RS, et al.Methods for imaging cell fates in hematopoiesis. Methods Mol Med,2007; 134:17-34.
[23]Ke YQ, Hu CC, Jiang XD, et al.In vivo magnetic resonance tracking of Feridex-labeled bone marrow-derived neural stem cells after autologous transplantation in rhesus monkey. J Neurosci Methods,2009;179(1):45-50.
[24]Neri M, Maderna C, Cavazzin C, et al. Efficient in vitro labeling of human neural precursor cells with superparamagnetic iron oxide particles:relevance for in vivo cell tracking. Stem Cells, 2008;26(2):505-16.
[25]Fernandes AM, Marinho PA, Sartore RC, et al.Successful scale-up of human embryonic stem cell production in a stirred microcarrier culture system. Braz J Med Biol Res,2009;42(6):515-22.
[26]Omori Y, Honmou O, Harada K, et al. Optimization of a therapeutic protocol for intravenous injection of human mesenchymal stem cells after cerebral ischemia in adult rats. Brain Res, 2008;1236:30-8.
[27]Arias-Carrion O, Yuan TF.Autologous neural stem cell transplantation:A new treatment option for Parkinson's disease? Med Hypotheses.2009; 23. [Epub ahead of print]
[28]Arbab AS, Bashaw LA, Miller BR, et al.Intracytoplasmic tagging of cells with ferumoxides and transfection agent for cellular magnetic resonance imaging after cell transplantation:methods and techniques. Transplantation,2003; 76(7):1123-30.
[29]Zhang Z, van den Bos EJ, Wielopolski PA, et al.In vitro imaging of single living human umbilical vein endothelial cells with a clinical 3 0-T MRI scanner. Magma,2005; 18(4):175-85.
[30]Frank JA, Miller BR, Arbab AS, et al.Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents.Radiology,2003; 228(2):480-7.
[31]Shapiro EM, Sharer K, Skrtic S, et al. In vivo detection of single cells by MRI. Magn Reson Med,2006;55(2):242-9.
[32]Smirnov P, Poirier-Quinot M, Wilhelm C, et al. In vivo single cell detection of tumor-infiltrating lymphocytes with a clinical 1.5 Tesla MRI system. Magn Reson Med,2008; 60(6):1292-7
[33]Montet-Abou K, Montet X, Weissleder R et al.Transfection agent induced nanoparticle cell loading. Mol Imaging,2005;4(3):165-171.
[34]Arbab AS, Yocum GT, Kalish H et al. Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. Blood,2004; 104(4):1217-1223.
[35]Arbab AS, Yocum GT, Wilson LB et al. Comparison of transfection agents in forming complexes with ferumoxides, cell labeling efficiency, and cellular viability. Mol Imaging,2004;3 (1):24-32.
[36]Ju S, Teng G, Zhang Y et al.In vitro labeling and MRI of mesenchymal stem cells from human umbilical cord blood. Magn Reson Imaging,2006; 24(5):611-617.
[37]Kaim AH, Jundt G, Wischer T, et al.Functional-morphologic MR imaging with ultrasmall superparamagnetic particles of iron oxide in acute and chronic soft-tissue infection:study in rats.Radiology,2003;227(1):169-74.
[38]Lutz AM, Weishaupt D, Persohn E, et al. Imaging of macrophages in soft-tissue infection in rats:relationship between ultrasmall superparamagnetic iron oxide dose and MR signal characteristics. Radiology,2005;234 (3):765-75.
[39]Farrell E, Wielopolski P, Pavljasevic P, et al. Effects of iron oxide incorporation for long term cell tracking on MSC differentiation in vitro and in vivo. Biochem Biophys Res Commun, 2008;369(4):1076-81.
[40]Smirnov P, Gazeau F, Beloeil JC, et al. Single-cell detection by gradient echo 9.4 T MRI:a parametric study. Contrast Media Mol Imaging,2006; 1(4):165-74.
[41]J. Xie, C. Xu, N. Kohler, et al.Controlled PEGylation of Monodisperse Fe3O4 Nanoparticlesfor Reduced Non-Specific Uptake by Macrophage Cells. Adv. Mater.2007; 19:3163-3166.
[42]Jin Xie, Chenjie Xu, Zhichuan Xu, et al.Linking Hydrophilic Macromolecules to Monodisperse Magnetite (Fe3O4) Nanoparticles via Trichloro-s-triazine. Chem Mater.2006;18 (23):5401-5403.
[43]Bihari P, Vippola M, Schultes S, et al. Optimized dispersion of nanoparticles for biological in vitro and in vivo studies. Part Fibre Toxicol.2008;5:14.
[44]Lacava LM, Lacava ZG, Da Silva MF, et al. Magnetic resonance of a dextran-coated magnetic fluid intravenously administered in mice. Biophys J,2001;80 (5):2483-6.
[45]Caramella D, Jin XN, Mascalchi M, et al. Liver and spleen enhancement after intravenous injection of carboxydextran magnetite:effect of dose, delay of imaging, and field strength in an ex vivo model. MAGMA.1996;4(3-4):225-30.
[46]Boutry S, Brunin S, Mahieu I, et al.Magnetic labeling of non-phagocytic adherent cells with iron oxide nanoparticles:a comprehensive study. Contrast Media Mol Imaging. 2008;;3(6):223-32.
[47]Kim BS, Qiu JM, Wang JP, et al.Magnetomicelles:composite nanostructures from magnetic nanoparticles and cross-linked amphiphilic block copolymers.Nano Lett,2005;5(10):1987-91.
[48]Huh YM, Jun YW, Song HT, et al.In vivo magnetic resonance detection of cancer by using multifunctional magnetic nanocrystals. J Am Chem Soc,2005;127(35):12387-91.
[49]S. Sun, H. Zeng.Size-Controlled Synthesis of Magnetite Nanoparticles.J Am Chem Soc, 2002;124(28):8204-8205.
[50]Xu C, Xu K, Gu H, et al.Dopamine as a robust anchor to immobilize functional molecules on the iron oxide shell of magnetic nanoparticles. J Am Chem Soc,2004;126(32):9938-9.
[51]Hawkins MJ, Soon-Shiong P, Desai N. Protein nanoparticles as drug carriers in clinical medicine. Adv Drug Deliv Rev,2008;60(8):876-885.
[52]Purcell M, Neault JF, Tajmir-Riahi HA. Interaction of Taxol with human serum albumin. Biochim Biophys Acta,2000;1478 (1):61-68.
[53]Paal K, Muller J, Hegedus L. High affinity binding of paclitaxel to human serum albumin. Eur J Biochem.2001;268 (7):2187-2191.
[54]Zhang C F,Cao J Q,Yin D Z,et al.Preparation and radiolabeling Of human serum albumin(HSA)-coated magnetite nanopartieles for magnetically targeted therapy.Applied Radiation and Isotopes,2004;61(6):1255-1259.
[55]HE Han-wei,LIU Hong-jiang,ZHOU Ke-chao,et al.Characteristics of magnetic Fe3O4 nanoparticles encapsulated with human serum albumin. Journal Central South University of Technology,2006;13:6-11.
[56]Gupta AK, Gupta M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials,2005;26(18):3995-4021.
[57]Jun YW, Huh YM, Choi JS, et al.Nanoscale size effect of magnetic nanocrystals and their utilization for cancer diagnosis via magnetic resonance imaging. J. Am. Chem. Soc,2005; 127 (16):5732-5733.
[58]Shen S, Liu Y, Huang P, et al.In vitro cellular uptake and effects of. Fe3O4 magnetic nanoparticles on HeLa cells. J Nanosci Nanotechnol,2009;9(5):2866-71.
[59]Xie J, Peng S, Brower N, et al. One-pot synthesis of monodisperse iron oxide nanoparticles for potential biomedical applications. Pure and Applied Chemistry,2006;78(5):1003-1014.
[60]Shah AJ, Parsons B, Pope I, et al. The clinical impact of magnetic resonance imaging in diagnosing focal hepatic lesions and suspected cancer. Clin Imaging,2009;33(3):209-12.
[61]Mainenti PP, Mancini M, Mainolfi C, et al. Detection of colo-rectal liver metastases: prospective comparison of contrast enhanced US, multidetector CT, PET/CT, and 1.5 Tesla MR with extracellular and reticulo-endothelial cell specific contrast agents. Abdom Imaging.2009; 27.[Epub ahead of print].
[62]Wang Y, Chen S, Yang D,et al. Stem cell transplantation:a promising therapy for Parkinson's disease. J Neuroimmune Pharmacol.2007;2(3):243-50.
[63]Miljan EA, Sinden JD. Stem cell treatment of ischemic brain injury. Curr Opin Mol Ther. 2009;11(4):394-403.
[64]Morita E, Watanabe Y, Ishimoto M, et al. A novel cell transplantation protocol and its appli-cation to an ALS mouse model.Exp Neurol,2008;213(2):431-8.
[65]Luft FC.Novel cell therapy for type 1 diabetes mellitus.J Mol Med,2009;87 (7):659-61.
[66]Peldschus K, Kaul M, Lange C, et al. Magnetic resonance imaging of single SPIO labeled mesenchymal stem cells at 3 Tesla.Rofo.2007;179(5):473-9.
[67]Janic B, Rad AM, Jordan EK, et al. Optimization and Validation of FePro Cell Labeling Method. PLoS ONE,2009;4 (6):e5873.
[68]Nadri S, Soleimani M, Hosseni RH,et al. An efficient method for isolation of murine bone marrow mesenchymal stem cells.Int. J. Dev. Biol,2007;51(8):723-729
[69]Soleimani M, Nadri S. A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat Protoc,2009;4(1):102-6.
[70]Magnitsky S, Watson DJ, Walton RM, etal. In vivo and ex vivo MRI detection of localized and disseminated neural stem cell grafts in the mouse brain. Neuroimage,2005;26(3):744-54.
[71]Li Z, Suzuki Y, Huang M, Cao F,etal. Comparison of reporter gene and iron particle labeling for tracking fate of human embryonic stem cells and differentiated endothelial cells in living subjects. Stem Cells,2008;26(4):864-73.
[72]Daadi MM, Li Z, Arac A, Molecular and Magnetic Resonance Imaging of Human Embryonic Stem Cell-Derived Neural Stem Cell Grafts in Ischemic Rat Brain.Mol Ther,2009; 12. [Epub ahead of print].
[73]Gao X, Zhang H, Takahashi T,etal. The Akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the MAPK and PKC pathways. J Neurochem,2008;105(3):943-55.
[74]Zhao H, Wang JQ, Shimohata T,etal. Conditions of protection by hypothermia and effects on apoptotic pathways in a rat model of permanent middle cerebral artery occlusion. J Neurosurg, 2007;107(3):636-41.
[75]Guzman R, Uchida N, Bliss TM,etal. Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proc Natl Acad Sci U S A, 2007;104(24):10211-6.
[76]Wilhelm C, Billotey C, Roger J, et al.Intracellular uptake of anionic superparamagnetic nanoparticles as a function of their surface coating. Biomaterials,2003;24(6):1001-1011.
[77]Moore A, Marecos E, Bogdanov Jr. A, et al. Tumoral distribution of long-circulating dextran-coated iron oxide nanoparticles in a rodent model. Radiology,2000;214(2):568-74.
[78]Hawkins MJ, Soon-Shiong P, Desai N. Protein nanoparticles as drug carriers in clinical medicine. Adv Drug Deliv Rev,2008;60(8):876-885.
[79]John TA, Vogel SM, Tiruppathi C, et al. Quantitative analysis of albumin uptake and transport in the rat microvessel endothelial monolayer. Am J Physiol Lung Cell Mol Physiol, 2003;284(1):L187-L196.
[80]Patil S, Sandberg A, Heckert E, et al. Protein adsorption and cellular uptake of cerium oxide nanoparticles as a function of zeta potential.Biomaterials,2007;28(31):4600-7.
[81]Limbach LK, Li Y, Grass RN,et al. Oxide nanoparticle uptake in human lung fibroblasts: effects of particle size, agglomeration, and diffusion at low concentrations.Environ Sci Technol, 2005;39(23):9370-9376.
[82]Weissleder R, Stark DD, Engelstad BL, et al. Superparamagnetic iron oxide: pharmacokinetics and toxicity. AJR Am J Roentgenol,1989; 152(1):167-73.
[83]Cheung JS, Chow AM, Hui ES, et al. Cell number quantification of USPIO-labeled stem cells by MRI:an in vitro study. EMBS 28th Annual International Conference of the IEEE. 2006;476-479.
[84]Roser M,scher D,issel T. Surface-modified biodegradable albumin nano-and microspheres. II:effect of surface charges on in vitro phagocytosis and biodistribution in rats.European Journal of Pharmaceutics and Biopharmaceutics,1998;46(3):255-263.
[85]Bourrinet P, Bengele HH, Bonnemain B, et al.Preclinical safety and pharmacokinetic profile of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent. Invest Radiol,2006;41(3):313-24.
[86]Price CJ, Wang D, Menon DK, Guadagno JV, Cleij M, Fryer T, Aigbirhio F, Baron JC, Warburton EA. Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke.2006;37:1749-1753.
[87]Dirnagl U. Inflammation in stroke:the good, the bad, and the unknown.Ernst Schering Res Found Workshop,2004;47(7):87-99.
[88]Kleinschnitz C, Bendszus M, Frank M, Solymosi L, Toyka KV, Stoll G. In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging. J Cereb Blood Flow Metab,2003;23(11):1356-61.
[89]Watkins SK, Egilmez NK, Suttles J, et al. IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol,2007; 178 (3):1357-62.
[90]Camargo MR, Venturini J, Vilani-Moreno FR, et al. Modulation of macrophage cytokine profiles during solid tumor progression:susceptibility to Candida albicans infection. BMC Infect Dis.2009;9:98.
[91]Siveen KS, Kuttan G. Role of macrophages in tumour progression. Immunol Lett,2009; 123 (2):97-102.
[92]Lin EY, Nguyen AV, Russell RG, et al. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy.J Exp Med,2001; 193(6):727-740.
[93]Condeelis J,Pollard JW. Macrophages:obligate partners for tumor cell migration, invasion, and metastasis. Cell,2006;124(2):263-266.
[94]Takanami I, Takeuchi K, Kodaira S. Tumor-associated macrophage infiltration in pulmonary adenocarcinoma:association with angiogenesis and poor prognosis.Oncology,1999;57(2): 138-42.
[95]O. Hauger, C. Delalande, C. Deminiere, B. et al.Nephrotoxic nephritis and obstructive nephropathy:evaluation with MR imaging enhanced with ultrasmall superparamagnetic iron oxide. Preliminary findings in a rat model,Radiology,2000;217(3):819-826.
[96]Allavena P, Sica A, Vecchi A, et al. The chemokine receptor switch paradigm and dendritic cell migration:its significance in tumor tissues. Immunol Rev,2000; 177:141-149.
[97]Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization:tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol,2002; 23(11):549-55.
[98]Donovan A,Brownlie A,Zhou Y,et al.Positional cloning of zebrafish ferroportinl identifies a conserved vertebrate iron exporter.Nature,2000;403:776-781.
[99]Delaby C,Pilard N,Goncalves AS,et al.Presence of the iron exporter ferroportin at the plasma membrane of maerophages is enhanced by iron loading and down-regulated by hepcidin.Blood, 2005;106(12):3979-3984.
[100]Nardin A, Abastado JP. Macrophages and cancer.Front Biosci,2008;13:3494-505.
[101]Van Ginderachter JA, Movahedi K, Van den Bossche J, et a 1.Macrophages, PPARs, and Cancer. PPAR Res.2008;2008:169414.
[102]Sica A, Larghi P, Mancino A, et al. Macrophage polarization in tumour progression. Semin Cancer Biol,2008;18(5):349-55.
[103]Leek RD, Landers RJ, Harris AL, et al. Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. Br J Cancer,1999;79(5-6): 991-5.
[104]Griffiths L, Binley K, Iqball S, et al.The macrophage-a novel system to deliver gene therapy to pathological hypoxia. Gene Ther,2000;7(3):255-62.
[105]Ohno S, Ohno Y, Suzuki N, et al. Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer. Anticancer Res,2004;24(5C):3335-42.
[106]Bingle L, Lewis CE, Corke KP, et al. Macrophages promote angiogenesis in human breast tumour spheroids in vivo.Brit J Cancer,2006;94(1):101-107.
[1]Terkivatan T, van den Bos IC, Hussain SM, et al. Focal nodular hyperplasia:lesion characteristics on state-of-the-art MRI including dynamic gadolinium-enhanced and superparamagnetic iron-oxide-uptake sequences in a prospective study.J Magn Reson Imaging. 2006;24:864-72.
[2]Rockall AG, Sohaib A, Harisinghani MG, et al.Diagnostic performance of nanoparticle-enhanced magnetic resonance imaging in the diagnosis of lymph node metastases in patients with endometrial and cervical cancer. J Clin Oncol.2005;23(12):2813-2821.
[3]Kaim AH, Wischer T, O'Reilly T, et al.MR imaging with ultrasmall superparamagnetic iron oxide particles in experimental soft-tissue infections in rats.Radiology,2002,225(3):808-14.
[4]Zhang Y, Dodd SJ, Hendrich KS, et al. Magnetic resonance imaging detection of rat renal transplant rejection by monitoring macrophage infiltration. Kidney Int,2000;58 (3):1300-10.
[5]Price CJ, Wang D, Menon DK, Guadagno JV, Cleij M, Fryer T, Aigbirhio F, Baron JC, Warburton EA. Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke,2006; 37(7):1749-1753.
[6]O. Hauger, C. Delalande, C. Deminiere, B. et al.Nephrotoxic nephritis and obstructive nephropathy:evaluation with MR imaging enhanced with ultrasmall superparamagnetic iron oxide. Preliminary findings in a rat model,Radiology,2000;217(3):819-826.
[7]Tang TY, Howarth SP, Miller SR, et al. The ATHEROMA (Atorvastatin Therapy:Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. J Am Coll Cardiol, 2009;53(22):2039-50.
[8]Leimgruber A, Berger C, Cortez-Retamozo V, et al. Behavior of endogenous tumor-associated macrophages assessed in vivo using a functionalized nanoparticle. Neoplasia,2009;11(5):459-68.
[9]Wilhelm C, Billotey C, Roger J, et al. Intracellular uptake of anionic superparamagnetic nanoparticles as a function of their surface coating. Biomaterials,2003;24(6):1001-11.
[10]Ferrucci JT, Stark DD. Iron oxide-enhanced MR imaging of the liver and spleen:review of the first 5 years. AJR Am J Roentgenol,1990;155(5):943-950.
[11]Schulze E, Ferrucci JT, Poss K, et al. Cellular uptake and trafficking of a prototypical magnetic iron oxide label in yitro.Invest Radiol,1995;30(10):604-610.
[12]Pratten MK, Lloyd JB. Pinocytosis and phagocytosis:the effect of size of a particulate substrate on its mode of capture by rat peritoneal macrophages cultured in vivo. Biochim Biophys Acta,1986;881(3):307-313.
[13]孔卫娜,段相林,常彦忠.单核巨噬细胞系统铁代谢调控机制.自然科学进展.2008;6:615-620.
[14]Donovan A,Brownlie A,Zhou Y,et al.Positional cloning of zebrafish ferroportinl identifies a conserved vertebrate iron exporter.Nature,2000;403(6771):776-781.
[15]Delaby C,Pilard N,Goncalves AS,et al.Presence of the iron exporter ferroportin at the plasma membrane of maerophages is enhanced by iron loading and down-regulated by hepcidin.Blood, 2005;106(12):3979-3984.
[16]Weissleder R, Stark DD, Engelstad BL, et al. Superparamagnetic iron oxide: pharmacokinetics and toxicity. AJR Am J Roentgenol,1989;152(1):167-73.
[17]Bourrinet P, Bengele HH, Bonnemain B, et al. Preclinical safety and pharmacokinetic profile of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent. Invest Radiol,2006;41(3):313-24.
[18]Bulte JW, Kraitchman DL.Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed,2004;7(7):484-99.
[19]Raynal I, Prigent P, Peyramaure S, et al. Macrophage endocytosis of superparamagnetic iron oxide nanoparticles:mechanisms and comparison of ferumoxides and ferumoxtran-10. Invest Radiol,2004;39(1):56-63.
[20]Wang YX, Hussain SM, Krestin GP. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol, 2001;11(11):2319-2331.
[21]Fleige G, Seeberger F, Laux D, et al. In vitro characterization of two different ultrasmall iron oxide particles for magnetic resonance cell tracking. Invest Radiol,2002;37(9):482-488.
[22]Arvind P. Pathak. Magnetic resonance susceptibility based perfusion imaging of tumors using iron oxide nanoparticles. WIREs Nanomedicine and Nanobiotechnology,2009; 1:84-97.
[23]Sosnovik DE, Nahrendorf M, Weissleder R. Magnetic nanoparticles for MR imaging:agents, techniques and cardiovascular applications. Basic Res Cardiol.2008; 103(2):122-30.
[24]Ma HL, Xu YF, Qi XR, et al.Superparamagnetic iron oxide nanoparticles stabilized by alginate:pharmacokinetics, tissue distribution, and applications in detecting liver cancers. Int J Pharm,2008,;354(1-2):217-26.
[25]Farrell E, Wielopolski P, Pavljasevic P, et al. Effects of iron oxide incorporation for long term cell tracking on MSC differentiation in vitro and in vivo. Biochem Biophys Res Commun, 2008;369(4):1076-81.
[26]Smirnov P, Gazeau F, Beloeil JC, et al. Single-cell detection by gradient echo 9.4 T MRI:a parametric study. Contrast Media Mol Imaging,2006; 1(4):165-74.
[27]Shapiro EM, Sharer K, Skrtic S, et al. In vivo detection of single cells by MRI. Magn Reson Med,2006;55(2):242-9.
[28]Heyn C, Ronald JA, Mackenzie LT, et al. In vivo magnetic resonance imaging of single cells in mouse brain with optical validation.Magn Reson Med,2006;55(1):23-29.
[29]Tsang YM, Stark DD, Chen MC, et al. Hepatic micrometastases in the rat:ferrite enhanced MR imaging. Radiology,1988;167(1):21-24.
[30]Shah AJ, Parsons B, Pope I, et al. The clinical impact of magnetic resonance imaging in diagnosing focal hepatic lesions and suspected cancer. Clin Imaging,2009;33(3):209-12.
[31]Mainenti PP, Mancini M, Mainolfi C, et al. Detection of colo-rectal liver metastases: prospective comparison of contrast enhanced US, multidetector CT, PET/CT, and 1.5 Tesla MR with extracellular and reticulo-endothelial cell specific contrast agents. Abdom Imaging.2009; 27.[Epub ahead of print].
[32]Paley MR, Mergo PJ, Torres GM, et al. Characterization of focal hepatic lesions with ferumoxides-enhanced T2-weighted MR imaging.AJR,2000;175(1):159-163.
[33]Zheng WW, Zhou KR, Chen ZW, et al.Characterization of focal hepatic lesions with SPIO-enhanced MRI. World J Gastroenterol,2002;8(1):82-6.
[34]Clement O, Frija G, Chambon C, et al. Liver tumors in cirrhosis:experimental study with SPIO-enhanced MR imaging. Radiology,1991;180(1):31-36.
[35]Elizondo G, Weissleder R, Stark DD, et al. Hepatic cirrhosis and hepatitis:MR imaging enhanced with superparamagnetic iron oxide.Radiology,1990; 174(3Pt1):797-801.
[36]Yamashita Y, Yamamoto H, Hirai A, et al.MR imaging enhancement with superparamagnetic iron oxide in chronic liver disease:influence of liver dysfunction and parenchymal pathology. Abdom Imaging,1996;21(4):318-23.
[37]Hahn PF, Weissleder R, Stark DD, et al. MR imaging of focal splenic tumors. AJR, 1988;150(4):823-7.
[38]Weissleder R, Hahn P, Stark D, et al. Superparamagnetic iron oxide:enhanced detection of focal splenic tumors with MR imaging. Radiology,1988;169(2):399-403.
[39]Harisinghani MG, Saini S, Weissleder R, et al. Splenic imaging with ultrasmall superparamagnetic iron oxide ferumoxtran-10 (AMI-7227):preliminary observations. J Comput Assist Tomogr,2001;25(5):770-6.
[40]Weissleder A, Stark DD, Rummeny EJ, et al. Splenic lymphoma:ferrite-enhanced MR imaging in rats. Radiology,1988;166(2):423-430.
[41]Kim SH, Lee JM, Han JK, et al. Intrapancreatic accessory spleen:findings on MR Imaging, CT, US and scintigraphy, and the pathologic analysis. Korean J Radiol,2008;9(2):162-74.
[42]Bellin MF, Roy C, Kinkel K, et al. Lymph node metastases:safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles-initial clinical experience.Radiology,1998;207(3):799-808.
[43]Pannu HK, Wang KP, Borman TL, et al. MR imaging of mediastinal lymph nodes: evaluation using a superparamagnetic contrast agent. J Magn Reson Imaging,2000; 12(6):899-904.
[44]Seneterre E, Weissleder R, Jaramillo D, et al. Bone marrow:ultrasmall superparamagnetic iron oxide for MR imaging.Radiology,1991;179(2):529-33.
[45]Bierry G, Jehl F, Boehm N, et al.Macrophage activity in infected areas of an experimental vertebral osteomyelitis model:USPIO-enhanced MR imaging-feasibility study.Radiology. 2008;248:114-23(1).
[46]Fukuda Y, Ando K, Ishikura R, et al. Superparamagnetic iron oxide (SPIO) MRI contrast agent for bone marrow imaging:differentiating bone metastasis and osteomyelitis. Magn Reson Med Sci,2006;5(4):191-6.
[47]Bierry G, Jehl F, Boehm N, Robert P, Dietemann JL, Kremer S. Macrophage imaging by USPIO-enhanced MR for the differentiation of infectious osteomyelitis and aseptic vertebral inflammation. Eur Radiol,2009; 19(7):1604-11.
[48]van den Brekel MW. Lymph node metastases:CT and MRI. Eur J Radiol,2000,33(3):230-8.
[49]Laissy JP, Gay-Depassier P, Soyer P, et al. Enlarged mediastinal lymph nodes in bronchogenic carcinoma:assessment with dynamic contrast-enhanced MR imaging. Radiology, 1994;191(1):263-7.
[50]Narayanan P, Iyngkaran T, Sohaib SA, et al. Magnetic resonance lymphography:a novel technique for lymph node assessment in gynecologic malignancies. Cancer Biomark,2009;5 (2):81-8.
[51]Misselwitz B.MR contrast agents in lymph node imaging. Eur J Radiol,2006;58 (3):375-82.
[52]Kimura K, Tanigawa N, Matsuki M, et al.High-resolution MR lymphography using ultrasmall superparamagnetic iron oxide (USPIO) in the evaluation of axillary lymph nodes in patients with early stage breast cancer:preliminary results.Breast Cancer.2009;3.[Epub ahead of print]
[53]Narayanan P, Iyngkaran T, Sohaib SA, et al.Pearls and pitfalls of MR lymphography in gynecologic malignancy. Radiographics,2009;29(4):1057-69.
[54]Xue HD, Lei J, Li Z, et al. Lymph node image with ultrasmall superparamagnetic iron oxide and comparison with pathological result. Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2009;31 (2):139-45.
[55]Kaim AH, Jundt G, Wischer T, et al.Functional-morphologic MR imaging with ultrasmall superparamagnetic particles of iron oxide in acute and chronic soft-tissue infection:study in rats.Radiology,2003;227(1):169-74.
[56]Lutz AM, Weishaupt D, Persohn E, et al. Imaging of macrophages in soft-tissue infection in rats:relationship between ultrasmall superparamagnetic iron oxide dose and MR signal characteristics. Radiology,2005;234(3):765-75.
[57]Lutz AM, Gopfert K, Jochum W, et al. USPIO-enhanced MR imaging for visualization of synovial hyperperfusion and detection of synovial macrophages:preliminary results in an experimental model of antigen-induced arthritis. J Magn Reson Imaging,2006;24(3):657-66.
[58]Simon GH, von Vopelius-Feldt J, Fu Y, et al.Ultrasmall supraparamagnetic iron oxide-enhanced magnetic resonance imaging of antigen-induced arthritis:a comparative study between SHU 555 C, ferumoxtran-10, and ferumoxytol. Invest Radiol,2006;41(1):45-51.
[59]Bar-Or A, Oliveira EM, Anderson DE, et al. Molecular pathogenesis of multiple sclerosis. J Neuroimmunol,1999;100(1-2):252-9.
[60]Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain.2009;132(Pt 5):1175-89.
[61]Baeten K, Hendriks JJ, Hellings N, et al.Visualisation of the kinetics of macrophage infiltration during experimental autoimmune encephalomyelitis by magnetic resonance imaging. J Neuroimmunol,2008;195(1-2):1-6.
[62]Stoll G, Bendszus M. Imaging of inflammation in the peripheral and central nervous system by magnetic resonance imaging. Neuroscience,2009; 158(3):1151-60.
[63]Brochet B, Deloire MS, Touil T, et al. Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE. Neuroimage,2006;32 (1):266-74.
[64]Floris S, Blezer EL, Schreibelt G, et al. Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis:a quantitative MRI study. Brain,2004; 127 (Pt 3):616-27.
[65]Dousset V, Brochet B, Deloire MS, et al. MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium. AJNR Am J Neuroradiol, 2006;27(5):1000-5.
[66]Kitchens WH, Chase CM, Uehara S, et al. Macrophage depletion suppresses cardiac allograft vasculopathy in mice. Am J Transplant,2007;7(12):2675-2682.,
[67]Pilmore HL, Painter DM, Bishop GA, et al. Early up-regulation of macrophages and myofibroblasts:a new marker for development of chronic renal allograft rejection. Transplantation,2000;69(12):2658-2662.
[68]Ye Q, Yang D, Williams M, et al. In vivo detection of acute rat renal allograft rejection by MRI with USPIO particles. Kidney Int,2002;61(3):1124-35.
[69]Beckmann N, Cannet C, Fringeli-Tanner M,et al. Macrophage labeling by SPIO as an early marker of allograft chronic rejection in a rat model of kidney transplantation. Magn Reson Med, 2003;49(3):459-467.
[70]Beckmann N, Cannet C, Zurbruegg S, et al. Macrophage infiltration detected at MR imaging in rat kidney allografts:early marker of chronic rejection? Radiology,2006;240(3):717-24.
[71]Kanno S, Lee PC, Dodd SJ, et al. A novel approach with magnetic resonance imaging used for the detection of lung allograft rejection. J Thorac Cardiovasc Surg,2000;120(5):923-34.
[72]Kanno S, Wu YJ, Lee PC, et al. Macrophage accumulation associated with rat cardiac allograft rejection detected by magnetic resonance imaging with ultrasmall superparamagnetic iron oxide particles. Circulation,2001;104(8):934-8.
[73]Ye Q, Foley LM, Hitchens TK, et al. In situ labeling of immune cells with iron oxide particles:an approach to detect organ rejection by cellular MRI. Proc Natl Acad Sci USA, 2006;103(6):1852-7.
[74]Ye Q, Wu YL, Foley LM, et al.Longitudinal tracking of recipient macrophages in a rat chronic cardiac allograft rejection model with noninvasive magnetic resonance imaging using micrometer-sized paramagnetic iron oxide particles. Circulation,2008; 118(2):149-56.
[75]Dirnagl U. Inflammation in stroke:the good, the bad, and the unknown.Ernst Schering Res Found Workshop.2004;47:87-99.
[76]Stoll G, Jander S, Schroeter M. Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol,1998;56(2):149-171.
[77]Kleinschnitz C, Bendszus M, Frank M, et al.Solymosi L, Toyka KV, Stoll G. In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging. J Cereb Blood Flow Metab,2003;23(11):1356-61.
[78]Saleh A, Schroeter M, Ringelstein A, et al.Hartung HP, Siebler M, Modder U, Jander S. Iron oxide particle-enhanced MRI suggests variability of brain inflammation at early stages after ischemic stroke. Stroke,2007;38(10):2733-7.
[79]Nighoghossian N, Wiart M, Cakmak S, et al. Inflammatory response after ischemic stroke:a USPIO-enhanced MRI study in patients. Stroke,2007;38(2):303-7.
[80]Jaffer FA, Sosnovik DE, Nahrendorf M, et al.Molecular imaging of myocardial infarction. J Mol Cell Cardiol,2006;41(6):921-33.
[81]Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res,2002;53(1):31-47.
[82]Leor J, Rozen L, Zuloff-Shani A, et al. Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart. Circulation,2006;114(1 Suppl):Ⅰ94-100.
[83]A.F. Catchpole, C.A. Carr, J.E. Schneider, et al. Contrast-enhanced MRI tracking of post-infarct myocardial macrophage infiltration.Journal of Molecular and Cellular Cardiology. 2006;6(40):921.
[84]Berr SS, Xu Y, Roy RJ, et al. Images in cardiovascular medicine. Serial multimodality assessment of myocardial infarction in mice using magnetic resonance imaging and micro-positron emission tomography provides complementary information on the progression of scar formation.Circulation,2007;115(17):e428-9.
[85]Sosnovik DE, Nahrendorf M, Deliolanis N, et al. Fluorescence tomography and magnetic resonance imaging of myocardial macrophage infiltration in infarcted myocardium in vivo.Circulation,2007;115(11):1384-91.
[86]O. Hauger, C. Delalande, H. Trillaud, C. et al. MR imaging of intrarenal macrophage inf iltration in an experimental model of nephrotic syndrome. Magn. Reson. Med,1999;41(1):156-162.
[87]Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med,1999; 340:115-126.
[88]Kooi ME, Cappendijk VC, Cleutjens KB, et al. Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation,2003;107(19):2453-8.
[89]Yuan C, Mitsumori LM, Ferguson MS, et al.In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. Circulation,2001;104(17):2051-2056.
[90]Tang T, Howarth SP, Miller SR, et al. Assessment of inflammatory burden contralateral to the symptomatic carotid stenosis using high-resolution ultrasmall, superparamagnetic iron oxide-enhanced MRI. Stroke,2006;37(9):2266-2270.
[91]Trivedi RA,Mallawarachi C, U-King-Im JM, et al. Identifying inflamed carotid plaques using in vivo USPIO-enhanced MR imaging to label plaque macrophages. Arterioscler Thromb Vasc Biol,2006;26(7):1601-1606.
[92]Morris JB, Olzinski AR, Bernard RE, et al. p38 MAPK inhibition reduces aortic ultrasmall superparamagnetic iron oxide uptake in a mouse model of atherosclerosis:MRI assessment. Arterioscler Thromb Vasc Biol,2008;28(2):265-71.
[93]Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation.Nature,2008;454 (7203):436-444.
[94]Condeelis J,Pollard JW. Macrophages:obligate partners for tumor cell migration, invasion, and metastasis. Cell,2006;124(2):263-266.
[95]Bingle L, Brown NJ, and Lewis CE. The role of tumour-associated macrophages in tumour progression:implications for new anticancer therapies.J Pathol,2002;196(3):254-265.
[96]Lin EY, Nguyen AV, Russell RG, et al. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy.J Exp Med,2001;193(6):727-740.
[97]Murdoch C, Muthana M, Coffelt SB, et al. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer,2008;8(8):618-631.
[98]De Palma M, Venneri MA, Galli R, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell,2005;8(3):211-226.