Exploring the relationship between anti-PEG IgM behaviors and PEGylated nanoparticles and its significance for accelerated blood clearance

• Published in: Journal of controlled release 2016-07, Vol.234, p.59-67
• Main Authors: Shiraishi, Kouichi, Kawano, Kumi, Maitani, Yoshie, Aoshi, Taiki, Ishii, Ken J., Sanada, Yusuke, Mochizuki, Shinichi, Sakurai, Kazuo, Yokoyama, Masayuki
• Format: Article
• Language: English
• Subjects: Accelerated blood clearance (ABC) phenomenon; Animals; Anti-PEG IgM antibody; Half-Life; Hydrophobic and Hydrophilic Interactions; Hydrophobicity of conjugates; Immunoglobulin M - blood; Liposomes; Male; Metabolic Clearance Rate; Mice, Inbred C57BL; Micelles; Nanoparticles - chemistry; PEG-liposomes; Peptides - chemistry; Peptides - pharmacokinetics; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polymeric micelles
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2016.05.010

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. [Display omitted]