Department of Radiology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
Division of Histology and Embryology, Department of Anatomy, Histology and Embryology, Medical University of Innsbruck, Müllerstrasse 59, 6020, Innsbruck, Austria.
Histochem Cell Biol. 2021 Jan;155(1):19-73. doi: 10.1007/s00418-020-01919-0. Epub 2020 Oct 11.
This multidisciplinary study examined the pharmacokinetics of nanoparticles based on albumin-DTPA-gadolinium chelates, testing the hypothesis that these nanoparticles create a stronger vessel signal than conventional gadolinium-based contrast agents and exploring if they are safe for clinical use. Nanoparticles based on human serum albumin, bearing gadolinium and designed for use in magnetic resonance imaging, were used to generate magnet resonance images (MRI) of the vascular system in rats ("blood pool imaging"). At the low nanoparticle doses used for radionuclide imaging, nanoparticle-associated metals were cleared from the blood into the liver during the first 4 h after nanoparticle application. At the higher doses required for MRI, the liver became saturated and kidney and spleen acted as additional sinks for the metals, and accounted for most processing of the nanoparticles. The multiple components of the nanoparticles were cleared independently of one another. Albumin was detected in liver, spleen, and kidneys for up to 2 days after intravenous injection. Gadolinium was retained in the liver, kidneys, and spleen in significant concentrations for much longer. Gadolinium was present as significant fractions of initial dose for longer than 2 weeks after application, and gadolinium clearance was only complete after 6 weeks. Our analysis could not account quantitatively for the full dose of gadolinium that was applied, but numerous organs were found to contain gadolinium in the collagen of their connective tissues. Multiple lines of evidence indicated intracellular processing opening the DTPA chelates and leading to gadolinium long-term storage, in particular inside lysosomes. Turnover of the stored gadolinium was found to occur in soluble form in the kidneys, the liver, and the colon for up to 3 weeks after application. Gadolinium overload poses a significant hazard due to the high toxicity of free gadolinium ions. We discuss the relevance of our findings to gadolinium-deposition diseases.
这项多学科研究考察了基于白蛋白-DTPA-钆螯合物的纳米颗粒的药代动力学，检验了这些纳米颗粒比传统的基于钆的对比剂产生更强的血管信号的假设，并探索了它们是否可安全用于临床。基于人血清白蛋白的纳米颗粒，带有钆，设计用于磁共振成像，用于生成大鼠血管系统的磁共振图像（“血池成像”）。在用于放射性核素成像的低纳米颗粒剂量下，纳米颗粒相关金属在纳米颗粒应用后 4 小时内从血液中清除到肝脏中。在用于 MRI 的较高剂量下，肝脏饱和，肾脏和脾脏成为金属的额外汇，并且占纳米颗粒的大部分处理。纳米颗粒的多个成分彼此独立清除。静脉注射后，白蛋白在肝脏、脾脏和肾脏中可检测到长达 2 天。钆在肝脏、肾脏和脾脏中以显著浓度保留的时间长得多。在应用后超过 2 周的时间内，初始剂量的相当一部分仍存在钆，并且只有在 6 周后才能完全清除钆。我们的分析无法对应用的全部钆剂量进行定量解释，但发现许多器官的结缔组织中的胶原蛋白中都含有钆。多条证据表明，细胞内处理打开 DTPA 螯合物并导致钆的长期储存，特别是在溶酶体中。在应用后长达 3 周的时间内，在肾脏、肝脏和结肠中发现以可溶性形式发生储存的钆的转化。由于游离的钆离子的高毒性，储存的钆的过度积累会带来重大危害。我们讨论了我们的发现对钆沉积疾病的相关性。
