Ganglioside inserted into PEGylated liposome attenuates anti-PEG immunity.
Despite the clinical introduction of a vast number of polyethylene glycol (PEG)-conjugated therapeutics, conjugated PEG is also known for an unfortunate inclination toward immunogenicity. Immunogenicity of PEG, manifested by the robust production of anti-PEG IgM, is known to compromise the therapeutic efficacy and/or reduce the tolerance of PEGylated therapeutics. In the present study, we inserted ganglioside into the membrane of PEGylated liposome (PL) to prepare ganglioside-modified PEGylated liposomes (G-PL), and investigated its efficacy in attenuating the anti-PEG IgM response against PL. A single intravenous injection of G-PL significantly attenuated the anti-PEG IgM production, compared with that of naïve PL. In addition, pretreatment with G-PL substantially alleviated the anti-PEG IgM response elicited by a subsequent dose of PL, presumably via inducing B cell tolerance, and as a consequence, this modification abrogated/attenuated the incidence of the rapid clearance of subsequently administrated PL. These results indicate that incorporating gangliosides in PEGylated liposome membrane not only prevents the immunogenicity of PEG but also induces the tolerance of B cells to subsequent doses of the immunogenic PL. Consequently, liposomal membrane modification with ganglioside might represent a promising approach to attenuating the immunogenicity of PEGylated liposomes while preserving their therapeutic efficacy, particularly upon repeated administration.
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
Yu
Y
Mima
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Department of Pharmaceutics, College of Pharmacy, Hail University, Hail 81442, Saudi Arabia.
Amr S
AS
Abu Lila
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
Taro
T
Shimizu
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
Masami
M
Ukawa
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan; Department of Cancer Metabolism and Therapy, Subdivision of Biopharmaceutical Sciences, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan.
Hidenori
H
Ando
Department of Pharmacy, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558, Japan.
Yasuko
Y
Kurata
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan; Department of Cancer Metabolism and Therapy, Subdivision of Biopharmaceutical Sciences, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan. Electronic address: ishida@tokushima-u.ac.jp.
Tatsuhiro
T
Ishida
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D065546:Drug Liberation; D005732:Gangliosides / Q000737:chemistry / Q000494:pharmacology*; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000276:immunology; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013499:Surface Properties
D005732:Gangliosides; D007075:Immunoglobulin M; D008081:Liposomes; D011092:Polyethylene Glycols
ABC phenomenon; Anti-PEG IgM; Ganglioside; PEGylated liposomes; Splenic B cells