title: Exploring the relationship between anti-PEG IgM behaviors and PEGylated nanoparticles and its significance for accelerated blood clearance.
abstract: 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.
authors.affiliation: Medical Engineering Laboratory, Research Center for Medical Sciences, Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Shiraishi
authors.affiliation: The Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kawano
authors.affiliation: The Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Maitani
authors.affiliation: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Asagi Saito, Ibaraki-City, Osaka 567-0085, Japan; Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center (IFREC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Vaccine Dynamics Project, BIKEN Innovative Vaccine Research Alliance Laboratories, the Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.affiliation: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Asagi Saito, Ibaraki-City, Osaka 567-0085, Japan; Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center (IFREC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.affiliation: The Department of Chemistry and Biochemistry, the University of Kitakyushu, 1-1 Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka, 808-0135, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sanada
authors.affiliation: The Department of Chemistry and Biochemistry, the University of Kitakyushu, 1-1 Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka, 808-0135, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mochizuki
authors.affiliation: The Department of Chemistry and Biochemistry, the University of Kitakyushu, 1-1 Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka, 808-0135, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakurai
authors.affiliation: Medical Engineering Laboratory, Research Center for Medical Sciences, Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address: masajun2093ryo@jikei.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D006207:Half-Life; D057927:Hydrophobic and Hydrophilic Interactions; D007075:Immunoglobulin M / Q000097:blood*; D008081:Liposomes; D008297:Male; D008657:Metabolic Clearance Rate; D008810:Mice, Inbred C57BL; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D007075:Immunoglobulin M; D008081:Liposomes; D008823:Micelles; D010455:Peptides; C000624623:polyethylene glycol-b-poly(beta-benzyl aspartate); D011092:Polyethylene Glycols
keywords: Accelerated blood clearance (ABC) phenomenon; Anti-PEG IgM antibody; Hydrophobicity of conjugates; PEG-liposomes; Polymeric micelles