Gibby Wendell, Parish Wes, Merrill Ray M, Fernandez Diego, Anderson Christopher R, Merchel Eric, Parr Ryan
Magnetic Research Inc., 3152 N University Ave #50, Provo, UT 84604, United States of America; University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States of America.
Magnetic Research Inc., 3152 N University Ave #50, Provo, UT 84604, United States of America.
Magn Reson Imaging. 2019 May;58:76-81. doi: 10.1016/j.mri.2019.01.001. Epub 2019 Jan 10.
Tissue and bone retention of gadolinium based contrast agents (GBCAs) has become a clinical concern because of the potential short and long term toxic effects of free gadolinium. This is a critical problem for most open-chain agents that more readily transmetallate in vivo, in comparison to macrocyclic compounds. Gadolinium diethylene tri-aminepentaacetic acid bis-glucosamide (Gd-DTPA-BIGA) is an experimental, open-chain contrast agent which has a significantly increased relaxivity coefficient in comparison to other GBCAs. This results in greater signal intensity and improved contrast enhancement. These superior imaging qualities initiated a search for a solution to the transmetallation of this agent. Plasma zinc is a well-known GBCA transmettalation agent. Since the base chelate of Gadodiamide (Gd-DPTA-Bis-Methylamide or Omniscan), DTPA-Bis-Methylamide (DTPA-BMA), readily transmettalates with and binds serum zinc, we hypothesized that a plasma "zinc sink," may significantly reduce transmetallation of linear agents. 5% DTPA-BMA was added to a formulation of Gd-DTPA-BIGA, which was tested against the original formulation of Gd-DTPA-BIGA with 0.2% of the base chelate DTPA-BIGA. These formulations, including gadodiamide, were labeled with GdCl followed by infusion into cohorts of Sprague Dawley rats which were sacrificed at 1, 30 and 60 days. Internal organs were harvested, along with blood, skin and femur, and analyzed for residual gadolinium. A subset of tissues were also interrogated with ICP-MS. Labeled Gadodiamide and saline where used as controls. Conclusion: The addition of 5% DTPA-BMA, as a zinc binding agent, reduced the transmetallation of the linear agent Gd-DTPA-BIGA, in comparison to its original formulation supplemented with 0.2% BIGA. This result indicates that supplementing linear GBCAs with ancillary chelates may hold promise for reducing, or eliminating the biological archiving of gadolinium in tissues. In addition, this paper provides valuable animal data on the long term retention of gadolinium from linear based contrast agents.
由于游离钆的潜在短期和长期毒性作用，钆基造影剂（GBCAs）在组织和骨骼中的滞留已成为一个临床关注点。与大环化合物相比，这对于大多数在体内更容易发生金属转移的开链造影剂来说是一个关键问题。钆二乙烯三胺五乙酸双葡糖酰胺（Gd-DTPA-BIGA）是一种实验性的开链造影剂，与其他GBCAs相比，其弛豫系数显著增加。这导致更高的信号强度和更好的对比度增强。这些卓越的成像质量引发了对解决该造影剂金属转移问题的探索。血浆锌是一种众所周知的GBCA金属转移剂。由于钆双胺（Gd-DPTA-双甲酰胺或欧乃影）的基础螯合物二乙烯三胺五乙酸双甲酰胺（DTPA-BMA）很容易与血清锌发生金属转移并结合，我们推测血浆“锌库”可能会显著减少线性造影剂的金属转移。将5%的DTPA-BMA添加到Gd-DTPA-BIGA制剂中，并与含有0.2%基础螯合物DTPA-BIGA的Gd-DTPA-BIGA原始制剂进行对比测试。这些制剂，包括钆双胺，用GdCl标记，然后注入斯普拉格-道利大鼠群体中，在1天、30天和60天时处死大鼠。采集内部器官以及血液、皮肤和股骨，并分析其中残留的钆。还使用电感耦合等离子体质谱法对一部分组织进行了检测。标记的钆双胺和生理盐水用作对照。结论：与补充了0.2%BIGA的原始制剂相比，添加5%DTPA-BMA作为锌结合剂，减少了线性造影剂Gd-DTPA-BIGA的金属转移。这一结果表明，用辅助螯合物补充线性GBCAs可能有望减少或消除钆在组织中的生物蓄积。此外，本文提供了关于线性造影剂中钆长期滞留的宝贵动物数据。
