Tyagi Priyanka, Kumar Amit, Gupta Dikshi, Singh Harpal
Center for Biomedical Engineering, Indian Institute of Technology, Delhi, 110016, India.
Department of Nuclear Medicine, Institute of Nuclear Medicine & Allied Sciences (INMAS), DRDO, Delhi, 110054, India.
AAPS PharmSciTech. 2017 Jan 1;18(1):156-165. doi: 10.1208/s12249-016-0499-x. Epub 2016 Feb 24.
Deferoxamine iron chelator has a limited therapeutic index due to rapid clearance from blood and possesses dose-limiting toxicity. Therefore, an intravenous deferoxamine delivery system based on dialdehyde cellulose (DAC) polymer was developed and its efficacy and toxicity were tested in iron-overloaded animals. The amino groups of deferoxamine were conjugated to free aldehyde moieties of dialdehyde cellulose via Schiff base reaction to form dialdehyde cellulose-deferoxamine (DAC-DFO) conjugate and characterized by Fourier transform infrared spectrophotometer, scanning electron microscope, and X-ray diffraction. The toxicity of prepared formulation was analyzed by XTT cell viability assay and LD50 study in mice. The change in serum iron levels, after intravenous administration of formulation, was observed in iron-overloaded rats. The DAC-DFO conjugate was tagged with Tc-99m to study the blood kinetics and observe change in blood circulation time. DAC-DFO conjugate was dispersible in water at concentration ∼75 mg/ml. In vitro cytotoxicity assay and LD study in mice indicated significantly enhanced safety of covalently bound deferoxamine (at >1000 mg/kg body weight compared to free drug at ∼270 mg/kg dose). A preliminary scintigraphy imaging and blood clearance study, with technetium-99m, indicated prolonged circulation of conjugated DFO in rabbit blood. A single dose of formulation injected into iron overloaded animals was found to maintain the normal serum iron levels until 10 days. The polymeric conjugate was effective in maintaining normal serum iron levels until 10 days at a dose of 100 mg/kg body weight.
去铁胺铁螯合剂由于从血液中快速清除，治疗指数有限，且具有剂量限制性毒性。因此，研发了一种基于二醛纤维素（DAC）聚合物的静脉注射去铁胺给药系统，并在铁过载动物中测试了其疗效和毒性。通过席夫碱反应将去铁胺的氨基与二醛纤维素的游离醛基共轭，形成二醛纤维素-去铁胺（DAC-DFO）共轭物，并通过傅里叶变换红外光谱仪、扫描电子显微镜和X射线衍射进行表征。通过XTT细胞活力测定和小鼠LD50研究分析了制备制剂的毒性。在铁过载大鼠中观察了静脉注射制剂后血清铁水平的变化。用Tc-99m标记DAC-DFO共轭物以研究血液动力学并观察血液循环时间的变化。DAC-DFO共轭物在浓度约为75 mg/ml时可分散于水中。体外细胞毒性测定和小鼠LD研究表明，共价结合的去铁胺安全性显著提高（与约270 mg/kg剂量的游离药物相比，体重>1000 mg/kg时）。用锝-99m进行的初步闪烁显像和血液清除研究表明，共轭DFO在兔血液中的循环时间延长。发现向铁过载动物注射单剂量制剂可使正常血清铁水平维持10天。该聚合物共轭物在体重100 mg/kg的剂量下可有效维持正常血清铁水平达10天。
