Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA.
Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA.
Int J Pharm. 2018 Mar 1;538(1-2):79-86. doi: 10.1016/j.ijpharm.2018.01.004. Epub 2018 Jan 16.
Deferoxamine (DFO) to treat iron overload (IO) has been limited by toxicity issues and short circulation times and it would be desirable to prolong circulation to improve non-transferrin bound iron (NTBI) chelation. In addition, DFO is currently unable to efficiently target the large pool of iron in the liver and spleen. Nanogel-Deferoxamine conjugates (NG-DFO) can prove useful as a model to investigate the pharmacokinetic (PK) properties and biodistribution (BD) behavior of iron-chelating macromolecules and their overall effect on serum ferritin levels. NG-DFO reduced the cytotoxicity of DFO and significantly reduced cellular ferritin levels in IO macrophages in vitro. PK/BD studies in normal rats revealed that NG-DFO displayed prolonged circulation and preferential accumulation into the liver and spleen. IO mice treated with NG1-DFO presented significantly lower levels of serum ferritin compared to DFO. Total renal and fecal elimination data point to the need to balance prolonged circulation with controlled degradation to accelerate clearance of iron-chelating macromolecules.
去铁胺（DFO）治疗铁过载（IO）受到毒性问题和短循环时间的限制，延长循环时间以改善非转铁蛋白结合铁（NTBI）螯合将是理想的。此外，DFO 目前无法有效地针对肝脏和脾脏中的大量铁池。纳米凝胶-去铁胺缀合物（NG-DFO）可作为一种模型，用于研究铁螯合大分子的药代动力学（PK）特性和生物分布（BD）行为及其对血清铁蛋白水平的整体影响。NG-DFO 降低了 DFO 的细胞毒性，并显著降低了 IO 巨噬细胞中的细胞铁蛋白水平。正常大鼠的 PK/BD 研究表明，NG-DFO 显示出延长的循环时间，并优先积累到肝脏和脾脏。与 DFO 相比，用 NG1-DFO 治疗的 IO 小鼠的血清铁蛋白水平显著降低。总肾和粪便消除数据表明，需要平衡延长的循环时间与控制降解，以加速铁螯合大分子的清除。
