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Magnetic Resonance Imaging Tracking of Ferumoxytol-Labeled Human Neural Stem Cells: Studies Leading to Clinical Use

机译:阿魏酸标记的人类神经干细胞的磁共振成像跟踪:导致临床使用的研究。

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摘要

Numerous stem cell-based therapies are currently under clinical investigation, including the use of neural stem cells (NSCs) as delivery vehicles to target therapeutic agents to invasive brain tumors. The ability to monitor the time course, migration, and distribution of stem cells following transplantation into patients would provide critical information for optimizing treatment regimens. No effective cell-tracking methodology has yet garnered clinical acceptance. A highly promising noninvasive method for monitoring NSCs and potentially other cell types in vivo involves preloading them with ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) to enable cell tracking using magnetic resonance imaging (MRI). We report here the preclinical studies that led to U.S. Food and Drug Administration approval for first-in-human investigational use of ferumoxytol to label NSCs prior to transplantation into brain tumor patients, followed by surveillance serial MRI. A combination of heparin, protamine sulfate, and ferumoxytol (HPF) was used to label the NSCs. HPF labeling did not affect cell viability, growth kinetics, or tumor tropism in vitro, and it enabled MRI visualization of NSC distribution within orthotopic glioma xenografts. MRI revealed dynamic in vivo NSC distribution at multiple time points following intracerebral or intravenous injection into glioma-bearing mice that correlated with histological analysis. Preclinical safety/toxicity studies of intracerebrally administered HPF-labeled NSCs in mice were also performed, and they showed no significant clinical or behavioral changes, no neuronal or systemic toxicities, and no abnormal accumulation of iron in the liver or spleen. These studies support the clinical use of ferumoxytol labeling of cells for post-transplant MRI visualization and tracking.
机译:目前,许多基于干细胞的疗法正在临床研究中,包括使用神经干细胞(NSC)作为将治疗剂靶向侵袭性脑肿瘤的递送载体。监测患者移植后干细胞的时程,迁移和分布的能力将为优化治疗方案提供关键信息。尚无有效的细胞追踪方法获得临床认可。一种非常有前途的非侵入性方法,用于在体内监测NSC和潜在的其他细胞类型,包括向它们预装超小型超顺磁性氧化铁纳米颗粒(USPIO),以使用磁共振成像(MRI)进行细胞跟踪。我们在这里报告了临床前研究,这些研究导致美国食品药品监督管理局批准在将人类抗坏血酸铁氧乙烯醚用于人脑干细胞标记之前在人类中进行首次研究性使用,然后再进行连续监测MRI。肝素,硫酸鱼精蛋白和阿魏酸(HPF)的组合用于标记NSC。 HPF标记在体外不影响细胞生存力,生长动力学或肿瘤嗜性,它使MRI可视化原位神经胶质瘤异种移植物中NSC的分布。 MRI揭示了脑内或静脉内注射到带有神经胶质瘤的小鼠体内后,多个时间点的体内NSC动态分布,这与组织学分析相关。还对小鼠经脑内注射HPF标记的NSC进行了临床前安全性/毒性研究,结果显示临床或行为无明显变化,无神经元或全身毒性,肝或脾中铁无异常蓄积。这些研究支持在临床上将阿魏酸标记细胞用于移植后MRI可视化和跟踪。

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