Vermeij Eline A, Koenders Marije I, Bennink Miranda B, Crowe Lindsey A, Maurizi Lionel, Vallée Jean-Paul, Hofmann Heinrich, van den Berg Wim B, van Lent Peter L E M, van de Loo Fons A J
Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Division of Radiology, Geneva University Hospitals, University of Geneva, Faculty of Medicine, Geneva, Switzerland.
PLoS One. 2015 May 8;10(5):e0126687. doi: 10.1371/journal.pone.0126687. eCollection 2015.
Superparamagnetic Iron Oxide Nanoparticles (SPION) are used in diagnostic imaging of a variety of different diseases. For such in-vivo application, an additional coating with a polymer, for example polyvinyl alcohol (PVA), is needed to stabilize the SPION and prevent aggregation. As the particles are foreign to the body, reaction against the SPION could occur. In this study we investigated the effects that SPION may have on experimental arthritis after intra-articular (i.a.) or intravenous (i.v.) injection.
PVA-coated SPION were injected either i.a. (6 or 24 μg iron) or i.v. (100 μg or 1 mg iron) into naïve Toll-like receptor-4 deficient (TLR4-/-) or wild-type C57Bl/6 mice, or C57Bl/6 mice with antigen-induced arthritis. As control, some mice were injected with PVA or PBS. MR imaging was performed at 1 and 7 days after injection. Mice were sacrificed 2 hours and 1, 2, 7, 10 and 14 days after injection of the SPION, and RNA from synovium and liver was isolated for pro-inflammatory gene expression analysis. Serum cytokine measurements and whole knee joint histology were also performed.
Injection of a high dose of SPION or PVA into naïve knee joints resulted in an immediate upregulation of pro-inflammatory gene expression in the synovium. A similar gene expression profile was observed after SPION or PVA injection into knee joints of TLR4-/- mice, indicating that this effect is not due to LPS contamination. Histological analysis of the knee joints also revealed synovial inflammation after SPION injection. Two hours after i.v. injection of SPION or PVA into naïve mice, an upregulation of pro-inflammatory gene expression was detected in the liver. Administration of SPION or PVA into arthritic mice via i.a. injection did not result in an upregulation in gene expression and also no additional effects were observed on histology. MR imaging and histology showed long-term retention of SPION in the inflamed joint. However, 14 days after the injections no long-term effects were evident for gene expression, histology or serum cytokine concentrations.
Injection of SPION, either locally or systemically, gives an acute inflammatory response. In the long term, up to 14 days after the injection, while the SPION reside in the joint, no further activating effects of SPION were observed. Hence, we conclude that SPION do not aggravate arthritis and can therefore be used safely to detect joint inflammation by MR imaging.
超顺磁性氧化铁纳米颗粒（SPION）用于多种不同疾病的诊断成像。对于这种体内应用，需要用聚合物（例如聚乙烯醇（PVA））进行额外包被，以稳定SPION并防止聚集。由于这些颗粒对于身体来说是外来的，可能会发生针对SPION的反应。在本研究中，我们调查了关节内（i.a.）或静脉内（i.v.）注射SPION后对实验性关节炎可能产生的影响。
将PVA包被的SPION以i.a.（6或24μg铁）或i.v.（100μg或1mg铁）的方式注射到未经处理的Toll样受体4缺陷（TLR4-/-）或野生型C57Bl/6小鼠，或抗原诱导性关节炎的C57Bl/6小鼠体内。作为对照，一些小鼠注射PVA或PBS。在注射后1天和7天进行磁共振成像。在注射SPION后2小时、1天、2天、7天、10天和14天处死小鼠，分离滑膜和肝脏的RNA用于促炎基因表达分析。还进行了血清细胞因子测量和全膝关节组织学检查。
向未经处理的膝关节注射高剂量的SPION或PVA导致滑膜中促炎基因表达立即上调。在向TLR4-/-小鼠的膝关节注射SPION或PVA后观察到类似的基因表达谱，表明这种效应不是由于LPS污染。膝关节的组织学分析也显示注射SPION后滑膜炎症。向未经处理的小鼠静脉注射SPION或PVA后2小时，在肝脏中检测到促炎基因表达上调。通过i.a.注射将SPION或PVA给予关节炎小鼠并未导致基因表达上调，并且在组织学上也未观察到额外的影响。磁共振成像和组织学显示SPION在炎症关节中长期留存。然而，注射后14天，在基因表达、组织学或血清细胞因子浓度方面没有明显的长期影响。
局部或全身注射SPION会引起急性炎症反应。从长期来看，在注射后长达14天，当SPION存在于关节中时，未观察到SPION的进一步激活作用。因此，我们得出结论，SPION不会加重关节炎，因此可以安全地用于通过磁共振成像检测关节炎症。
