Hemoglobin Vesicles, Polyethylene Glycol (PEG)ylated Liposomes Developed as a Red Blood Cell Substitute, Do Not Induce the Accelerated Blood Clearance Phenomenon in Mice
Hemoglobin Vesicles, Polyethylene Glycol (PEG)ylated Liposomes Developed as a Red Blood Cell Substitute, Do Not Induce the Accelerated Blood Clearance Phenomenon in Mice
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DOI：
10.1124/dmd.109.028852
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发表时间：
2009-11-01
影响因子：
3.9
通讯作者：
Otagiri, Masaki
中科院分区：
文献类型：
--
作者：
Taguchi, Kazuaki;Urata, Yukino;Otagiri, Masaki
血红蛋白囊泡（HbV）是一种人工氧载体，将浓缩血红蛋白溶液包裹在脂质体中，脂质体表面覆盖聚乙二醇（PEG）。最近有报道称，反复注射聚乙二醇脂质体可诱导加速血液清除（ABC）现象，其中血清抗聚乙二醇IgM起重要作用。为了研究这个问题，我们研究了HbV是否在0.1 mg Hb/kg的剂量下（通常已知会诱导ABC现象）或在1400 mg Hb/kg的剂量下（建议用于临床使用）诱导小鼠ABC现象。在第一次注射非标记HbV (0.1 mg Hb/kg) 7天后，小鼠接受Hb标记为I-125的HbV。第二次注射后，HbV迅速从循环中清除，肝脏和脾脏的摄取清除率显著增加。相反，在1400mg Hb/kg的剂量下，重复注射对HbV的药代动力学的影响可以忽略不计。值得注意的是，上述两种剂量注射后7天均产生抗HbV的IgM，并确定其在HbV中的识别位点为1,2-二硬脂酰-sn-甘油-3-磷脂酰乙醇胺- n- peg。这些结果表明，临床剂量的HbV不会诱导ABC现象，ABC现象的抑制是由单核吞噬细胞系统吞噬加工的饱和引起的。因此，我们得出结论，在临床使用的剂量方案中，ABC现象的诱导不会是一个问题。
The hemoglobin vesicle (HbV) is an artificial oxygen carrier encapsulating a concentrated hemoglobin solution in a liposome of which the surface is covered with polyethylene glycol (PEG). It was recently reported that repeated injections of PEGylated liposomes induce the accelerated blood clearance (ABC) phenomenon, in which serum anti-PEG IgM plays an essential role. To examine this issue, we investigated whether HbV induces the ABC phenomenon in mice at a dose of 0.1 mg Hb/kg, a dose that is generally known to induce the ABC phenomenon, or at 1400 mg Hb/kg, which is proposed for clinical use. At 7 days after the first injection of nonlabeled HbV (0.1 mg Hb/kg), the mice received HbV in which the Hb had been labeled with I-125. After a second injection, HbV was rapidly cleared from the circulation, and uptake clearances in liver and spleen were significantly increased. In contrast, at a dose of 1400 mg Hb/kg, the pharmacokinetics of HbV was negligibly affected by repeated injection. It is interesting to note that IgM against HbV was produced 7 days postinjection at both of the above doses, and their recognition site was determined to be 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-PEG in HbV. These results suggest that a clinical dose of HbV does not induce the ABC phenomenon, and that suppression of ABC phenomenon is caused by the saturation of phagocytic processing by the mononuclear phagocyte system. Thus, we conclude that induction of the ABC phenomenon would not be an issue in the dose regimen used in clinical settings.