Medical Engineering Laboratory, Research Center for Medical Sciences, Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
The Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
J Control Release. 2016 Jul 28;234:59-67. doi: 10.1016/j.jconrel.2016.05.010. Epub 2016 May 6.
Surface PEGylation on nanoparticles has greatly helped prolong their blood circulation half-lives. However, The injection of PEGylated nanoparticles into mice induced poly(ethylene glycol) (PEG)-specific IgM antibodies (anti-PEG IgMs), significantly changing PEG-liposomes' pharmacokinetics. In this study, we used various PEG-conjugates to conduct a mechanistic study of anti-PEG IgMs' binding behavior. The conventional belief has been that anti-PEG IgMs bind to PEG main chains; however, our findings reveal that anti-PEG IgMs did not bind to PEG main chains, whereas anti-PEG IgMs did bind to PEG-hydrophobic polymer blocks. The insertion of a hydrophilic polymer between each PEG chain and each hydrophobic polymer block suppressed anti-PEG IgMs' binding. We prove here that hydrophobic blocks are essential to anti-PEG IgMs' binding, and also that anti-PEG IgMs do not bind to intact PEGs without hydrophobic moiety. These results support our conclusion that anti-PEG IgMs exhibit specificity to PEG; however, the presence of a hydrophobic block at a proximity position from each PEG chain is essential for the binding. Also in the present study, we elucidate relations between anti-PEG IgMs and PEGylated nanoparticles. In one of our previous studies, anti-PEG IgMs scarcely affected the pharmacokinetics of PEG-b-poly(β-benzyl l-aspartate) block copolymer (PEG-PBLA) micelles, whereas anti-PEG IgMs significantly decreased PEG-liposomes' blood circulation half-life. Finally, we found that the ratio of anti-PEG IgM molecules to PEG-liposome particles is critical to these pharmacokinetic changes, and that a 10-fold increase in the number of anti-PEG IgM molecules permitted them to capture the PEG-liposome particles, thus leading to the aforementioned changes.
纳米粒子表面的聚乙二醇化极大地帮助延长了它们的血液循环半衰期。然而，将聚乙二醇化纳米粒子注射到小鼠中会诱导聚乙二醇特异性 IgM 抗体（抗-PEG IgM），从而显著改变聚乙二醇脂质体的药代动力学。在这项研究中，我们使用各种聚乙二醇缀合物来进行抗-PEG IgM 结合行为的机制研究。传统观点认为，抗-PEG IgM 结合到聚乙二醇主链上；然而，我们的发现表明，抗-PEG IgM 没有与聚乙二醇主链结合，而是与聚乙二醇疏水性聚合物块结合。在每个聚乙二醇链和每个疏水性聚合物块之间插入亲水性聚合物抑制了抗-PEG IgM 的结合。我们在这里证明，疏水性块对于抗-PEG IgM 的结合是必不可少的，并且没有疏水性部分的完整聚乙二醇也不会与抗-PEG IgM 结合。这些结果支持我们的结论，即抗-PEG IgM 对聚乙二醇表现出特异性；然而，每个聚乙二醇链附近位置的疏水性块的存在对于结合是必不可少的。在本研究中，我们还阐明了抗-PEG IgM 与聚乙二醇化纳米粒子之间的关系。在我们之前的一项研究中，抗-PEG IgM 对聚乙二醇-b-聚（β-苄基 L-天冬氨酸）嵌段共聚物（PEG-PBLA）胶束的药代动力学几乎没有影响，而抗-PEG IgM 显著降低了 PEG 脂质体的血液循环半衰期。最后，我们发现抗-PEG IgM 分子与 PEG 脂质体颗粒的比例对于这些药代动力学变化至关重要，并且抗-PEG IgM 分子数量增加 10 倍使它们能够捕获 PEG 脂质体颗粒，从而导致了上述变化。
