Relationship between the Concentration of Anti-polyethylene Glycol (PEG) Immunoglobulin M (IgM) and the Intensity of the Accelerated Blood Clearance (ABC) Phenomenon against PEGylated Liposomes in Mice
Relationship between the Concentration of Anti-polyethylene Glycol (PEG) Immunoglobulin M (IgM) and the Intensity of the Accelerated Blood Clearance (ABC) Phenomenon against PEGylated Liposomes in Mice
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DOI：
10.1248/bpb.b14-00653
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发表时间：
2015-03-01
影响因子：
2
通讯作者：
Kiwada, Hiroshi
中科院分区：
文献类型：
--
作者：
Hashimoto, Yosuke;Shimizu, Taro;Kiwada, Hiroshi
聚乙二醇化是用聚乙二醇（PEG）对纳米载体进行表面修饰，其增加了循环时间并降低了对纳米载体的免疫原性应答。然而，许多报告已经证明，静脉注射空间稳定的聚乙二醇化脂质体（SL）通过抗PEG免疫球蛋白M（IgM）介导的补体激活导致后续剂量的加速血液清除（ABC）。在本研究中，血清抗PEG IgM浓度，补体激活的强度和SL的肝清除率之间的关系进行了定量研究，它们在ABC现象的作用。有趣的是，随着血清抗PEG IgM浓度的增加，补体激活的强度线性增加，而SL的肝脏清除的强度增加，然后饱和。此外，不同剂量SL诱导的血液循环中仅15-17%的抗PEG IgM与第二剂量SL相关。目前的结果表明，这是SL的肝摄取，是ABC现象的限制步骤，而不是抗PEG IgM的SL和随后的补体激活的协会。
PEGylation, which is the surface modification of nanocarriers with polyethylene glycol (PEG), has increased the circulation time and reduced the immunogenic responses to nanocarriers. However, many reports have demonstrated that the intravenous injection of sterically stabilized PEGylated liposome (SL) causes an accelerated blood clearance (ABC) of subsequent doses via anti-PEG immunoglobulin M (IgM)-mediated complement activation. In the present study, the relationships between serum anti-PEG IgM concentration, the intensity of complement activation and the hepatic clearance of SL were quantitatively investigated for their role in the ABC phenomenon. Interestingly, with increasing serum anti-PEG IgM concentrations, the intensity of complement activation increased linearly, while the intensity of the hepatic clearance of SL was increased and then saturated. In addition, only 15-17% of anti-PEG IgM in blood circulation induced by SL at different doses was associated with a second dose SL. The present results indicate that it is the hepatic uptake of SL that is the limiting step in the ABC phenomenon, rather than the association of anti-PEG IgM to the SL and a subsequent complement activation.