From the *Clinic of Diagnostic and Interventional Radiology, Saarland University Medical Center, Homburg/Saar, Germany; †Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany; ‡Institut Lumière Matière, Université Claude Bernard Lyon 1, CNRS, Lyon, France; §Department of Radiotherapy and Radiation Oncology, Saarland University Medical Center, Homburg/Saar, Germany; and ∥Division of Plastic Surgery and Hand Surgery, University Hospital Zürich, University of Zürich, Zürich, Switzerland.
Invest Radiol. 2017 Dec;52(12):725-733. doi: 10.1097/RLI.0000000000000398.
Magnetic resonance lymphography (MRL) in small animals is a promising but challenging tool in preclinical lymphatic research. In this study, we compared the gadolinium (Gd)-based nanoparticle AGuIX with Gd-DOTA for interstitial MRL in healthy rats and in a chronic rat hindlimb lymphedema model.
A comparative study with AGuIX and Gd-DOTA for interstitial MRL was performed in healthy Lewis rats (n = 6). For this purpose, 75 μL of 3 mM AGuIX (containing 30 mM Gd-DOTA side residues) and 75 μL 30 mM Gd-DOTA were injected simultaneously in the right and left hindlimbs. Repetitive high-resolution, 3-dimensional time-of-flight gradient recalled echo MRL sequences were acquired over a period of 90 minutes using a 9.4 T animal scanner. Gadofosveset-enhanced MR angiography and surgical dissection after methylene blue injection served as supportive imaging techniques. In a subsequent proof-of-principle study, AGuIX-based MRL was investigated in a hindlimb model of chronic lymphedema (n = 4). Lymphedema of the right hindlimbs was induced by means of popliteal and inguinal lymphadenectomy and irradiation with 20 Gy. The nonoperated left hindlimbs served as intraindividual controls. Six, 10, and 14 weeks after lymphadenectomy, MRL investigations were performed to objectify lymphatic reorganization. Finally, skin samples of the lymphedematous and the contralateral control hindlimbs were analyzed by means of histology and immunohistochemistry.
AGuIX-based MRL resulted in high-resolution anatomical depiction of the rodent hindlimb lymphatic system. Signal-to-noise ratio and contrast-to-noise ratio of the popliteal lymph node were increased directly after injection and remained significantly elevated for up to 90 minutes after application. AGuIX provided significantly higher and prolonged signal intensity enhancement as compared with Gd-DOTA. Furthermore, AGuIX-based MRL demonstrated lymphatic regeneration in the histopathologically verified chronic lymphedema model. Collateral lymphatic vessels were detectable 6 weeks after lymphadenectomy.
This study demonstrates that AGuIX is a suitable contrast agent for preclinical interstitial MRL in rodents. AGuIX yields anatomical imaging of lymphatic vessels with diameters greater than 200 μm. Moreover, it resides in the lymphatic system for a prolonged time. AGuIX may therefore facilitate high-resolution MRL-based analyses of the lymphatic system in rodents.
磁共振淋巴造影（MRL）在小动物中是一种很有前途但具有挑战性的工具，可用于临床前淋巴研究。本研究比较了镓（Gd）基纳米颗粒 AGuIX 与 Gd-DOTA 在健康大鼠和慢性大鼠后肢淋巴水肿模型中的应用。
在健康的 Lewis 大鼠中进行了 AGuIX 与 Gd-DOTA 用于间质 MRL 的对比研究（n = 6）。为此，同时在右侧和左侧后肢注射 75 μL 3 mM AGuIX（含 30 mM Gd-DOTA 侧残基）和 75 μL 30 mM Gd-DOTA。使用 9.4 T 动物扫描仪在 90 分钟的时间内获取重复的高分辨率、3 维时飞梯度回波 MRL 序列。钆夫赛特增强磁共振血管造影和亚甲蓝注射后的手术解剖作为辅助成像技术。在随后的原理验证研究中，在慢性淋巴水肿的后肢模型中研究了基于 AGuIX 的 MRL（n = 4）。通过腘窝和腹股沟淋巴结切除术和 20 Gy 照射诱导右侧后肢淋巴水肿。未手术的左侧后肢作为个体内对照。淋巴结切除术后 6、10 和 14 周进行 MRL 检查以客观评估淋巴重组。最后，通过组织学和免疫组织化学分析，分析淋巴水肿和对侧对照后肢的皮肤样本。
AGuIX 基础 MRL 可实现高分辨率的啮齿动物后肢淋巴系统解剖学描述。注射后直接提高了隐窝淋巴结的信噪比和对比噪声比，应用后长达 90 分钟仍保持显著升高。与 Gd-DOTA 相比，AGuIX 提供了更高和更长时间的信号强度增强。此外，AGuIX 基础 MRL 在经组织病理学验证的慢性淋巴水肿模型中显示出淋巴再生。淋巴结切除术后 6 周即可检测到侧支淋巴管。
本研究表明，AGuIX 是一种适用于啮齿动物临床前间质 MRL 的造影剂。AGuIX 可对直径大于 200 μm 的淋巴管进行解剖成像。此外，它在淋巴系统中存在时间较长。因此，AGuIX 可能有助于进行基于高分辨率 MRL 的啮齿动物淋巴系统分析。
