MODULATION OF DEFEROXAMINE TOXICITY AND CLEARANCE BY COVALENT ATTACHMENT TO BIOCOMPATIBLE POLYMERS
MODULATION OF DEFEROXAMINE TOXICITY AND CLEARANCE BY COVALENT ATTACHMENT TO BIOCOMPATIBLE POLYMERS
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DOI：
10.1073/pnas.86.24.10108
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发表时间：
1989-12-01
影响因子：
11.1
通讯作者：
HEDLUND, BE
中科院分区：
文献类型：
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作者：
HALLAWAY, PE;EATON, JW;HEDLUND, BE
通过脱铁胺(DFO)的氨基与多种生物相容性聚合物(如葡聚糖和羟乙基淀粉)的共价连接，制备了一类高相对分子质量的铁络合剂。DFO的铁结合性能在附着过程后几乎没有变化，但其毒性和循环半衰期发生了深刻的变化。竞争性铁结合实验表明，所合成的偶联物对铁具有较高的亲和力。此外，这些衍生物与母药一样有效地抑制铁驱动的脂质过氧化。然而，小鼠的LD50(基于DFO当量)是.apprxeq。葡聚糖-DFO为4000 mg/kg，而游离DFO为250 mg/kg。与大大降低的LD50一致，狗静脉注射100 mg/kg(体重)的结合物不会导致与静脉注射DFO相关的严重低血压。与游离药物相比，葡聚糖-DFO和羟乙基淀粉-DFO的这些加合物的血浆半衰期增加了10倍。最后，也是最重要的是，这些结合物在调节体内铁动员和排泄方面是有效的。由于最近的证据表明铁是许多疾病状态下组织损伤的重要组成部分，这些高分子量铁螯合剂可能有改进治疗的潜力，允许更高的活性药物的持续血浆浓度。
A class of high molecular weight iron chelators has been prepared by covalently attaching deferoxamine (DFO), by its amino group, to a variety of biocompatible polymers such as dextran and hydroxyethyl-starch. The iron-binding properties of DFO are virtually unchanged after the attachment procedure, but the toxicity and circulatory half-life are profoundly altered. Competitive iron-binding experiments indicate that the conjugates retain a high affinity for ferric iron. In addition, the derivatives inhibit iron-driven lipid peroxidation as effectively as the parent drug. However, the LD50 in mice (based on DFO equivalents) is .apprxeq. 4000 mg/kg for dextran-DFO as compared to 250 mg/kg for free DFO. Consistent with the greatly decreased LD50, intravenous administration of the conjugates in dogs at a dose of 100 mg/kg (body weight) does not cause the severe hypotension associated with intravenous administration of DFO. The plasma half-lives of these adducts are increased >10-fold for dextran-DFO and hydroxethyl-starch-DFO compared to the free drug. Finally, and most importantly, the conjugates are effective in mediating in vivo iron mobilization and excretion. Because recent evidence implicates iron as an important component of tissue injury in many disease states, these high molecular weight iron chelators may have potential for improved therapy, allowing higher sustained plasma concentrations of the active drug.