Injections of polyethylene glycol (PEG)-modified nanomedicines can lead to an accelerated clearance of the next dose of PEGylated nanomedicines, which is referred to as the accelerated blood clearance (ABC) phenomenon. It has been reported that anti-PEG IgM plays an important role in the induction of the ABC phenomenon, identifying the interface between the main chain of PEG and the hydrophobic segment of the repeated injections of the PEGylated nanocarriers, resulting in increased liver uptake and loss of long-cycle characteristics. In this study, we demonstrated that the 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) in PEGylated nanoemulsions (PEs) may mask this interface between the main chain of PEG and the hydrophobic segment, inhibiting the recognition and binding of anti-PEG IgM to PEs, and evidently weakening the ABC phenomenon of PEs. This will provide a novel strategy to improve the curative effect of PEGylated nanocarriers.
PEGylated nanoemulsions (PEs) with 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) induced weakened the accelerated blood clearance (ABC) phenomenon in Wistar rats during repeated injection of PEs.
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D’Souza AA, Shegokar R. Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications. Expert Opin Drug Deliv. 2016;13(9):1257–75. https://doi.org/10.1080/17425247.2016.1182485.
Torchilin VP. Polymer-coated long-circulating microparticulate pharmaceuticals. J Microencapsul. 1998;15(1):1–19. https://doi.org/10.3109/02652049809006831.
Abuchowski A, van Es TV, Palczuk NC, Davis FF. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J Biol Chem. 1977;252(11):3578–81.
Abuchowski A, McCoy JR, Palczuk NC, van Es TV, Davis FF. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J Biol Chem. 1977;252(11):3582–6.
Roberts MJ, Bentley MD, Harris JM. Chemistry for peptide and protein pegylation. Adv Drug Deliv Rev. 2002;54(4):459–76. https://doi.org/10.1016/s0169-409x(02)00022-4.
Armstrong JK, Hempel G, Koling S, Chan LS, Fisher T, Meiselman HJ, et al. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer. 2007;110(1):103–11. https://doi.org/10.1002/cncr.22739.
Hershfield MS, Ganson NJ, Kelly SJ, Scarlett EL, Jaggers DA, Sundy JS. Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients. Arthritis Res Ther. 2014;16(2):R63. https://doi.org/10.1186/ar4500.
Mohamed M, Abu Lila AS, Shimizu T, Alaaeldin E, Hussein A, Sarhan HA, et al. Pegylated liposomes: immunological responses. Sci Technol Adv Mater. 2019;20(1):710–24. https://doi.org/10.1080/14686996.2019.1627174.
Liu Y, Smith CA, Panetta JC, Yang W, Thompson LE, Counts JP, et al. Antibodies predict pegaspargase allergic reactions and failure of rechallenge. J Clin Oncol. 2019;37(23):2051–61.
Dams ET, Laverman P, Oyen WJ, Storm G, Scherphof GL, van Der Meer JW, Corstens FH, Boerman OC. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J Pharmacol Exp Ther. 2000;292(3):1071–9.
Mima Y, Hashimoto Y, Shimizu T, Kiwada H, Ishida T. Anti-PEG IgM is a major contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein. Mol Pharm. 2015;12(7):2429–35.
Su Y, Liu M, Xiong Y, Ding J, Liu X, Song Y, et al. Effects of stability of pegylated micelles on the accelerated blood clearance phenomenon. Drug Deliv Transl Res. 2019;9(1):66–75.
Hara E, Ueda M, Makino A, Hara I, Ozeki E, Kimura S. Factors influencing in vivo disposition of polymeric micelles on multiple administrations. ACS Med Chem Lett. 2014;5(8):873–7.
Liu M, Chu Y, Liu H, Su Y, Zhang Q, Jiao J, et al. Accelerated blood clearance of nanoemulsions modified with PEG-cholesterol and PEG-phospholipid derivatives in rats: the effect of PEG-lipid linkages and PEG molecular weights. Mol Pharm. 2020;17(4):1059–70.
Joshi M, Pathak S, Sharma S, Patravale V. Solid microemulsion preconcentrate (NanOsorb) of artemether for effective treatment of malaria. Int J Pharm. 2008;362(1–2):172–8.
Lu W, Wan J, She Z, Jiang X. Brain delivery property and accelerated blood clearance of cationic albumin conjugated pegylated nanoparticle. J Control Release. 2007;118(1):38–53.
Zhang P, Sun F, Liu S, Jiang S. Anti-PEG antibodies in the clinic: current issues and beyond pegylation. J Control Release. 2016;244(B):184–93.
Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly (ethylene glycol) (PEG), in a phase I trial of subcutaneous pegylated urate oxidase. Arthritis Res Ther. 2006;8(1):R12.
Lipsky PE, Calabrese LH, Kavanaugh A, Sundy JS, Wright D, Wolfson M, et al. Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout. Arthritis Res Ther. 2014;16(2):R60.
Rau RE, Dreyer ZA, Choi MR, Liang W, Skowronski R, Allamneni KP, et al. Outcome of pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma with hypersensitivity to pegaspargase treated with pegylated Erwinia asparaginase, pegcrisantaspase: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2018;65(3).
Park K. Attenuating the immunogenicity of PEGylated liposomes by gangliosides. Journal of controlled release : official journal of the Controlled Release Society. 2017;250:116. https://doi.org/10.1016/j.jconrel.2017.03.002.
Zhang T, Zhou S, Kang L, Luo X, Liu Y, Song Y, et al. The effect of monosialylganglioside mix modifying the pegylated liposomal epirubicin on the accelerated blood clearance phenomenon. Asian J Pharm Sci. 2017;12(2):134–42. https://doi.org/10.1016/j.ajps.2016.06.005.
Mcsweeney MD, Price LSL, Wessler T, Ciociola EC, Herity LB, Piscitelli JA, et al. Overcoming anti-PEG antibody mediated accelerated blood clearance of pegylated liposomes by pre-infusion with high molecular weight free PEG. J Control Release. 2019;311–312(21):138–46.
Koide H, Asai T, Hatanaka K, Urakami T, Ishii T, Kenjo E, et al. Particle size-dependent triggering of accelerated blood clearance phenomenon. Int J Pharm. 2008;362(1–2):197–200.
Bavli Y, Winkler I, Chen BM, Roffler S, Cohen R, Szebeni J, et al. Doxebo (doxorubicin-free Doxil-like liposomes) is safe to use as a pre-treatment to prevent infusion reactions to pegylated nanodrugs. J Control Release. 2019;306(Suppl 4):138–48.
Li CL, Zhao X, Wang YJ, Yang HY, Li HX, Li H, et al. Prolongation of time interval between doses could eliminate accelerated blood clearance phenomenon induced by pegylated liposomal topotecan. Int J Pharm. 2013;443(1–2):17–25.
Ohmae M, Kojima M, Mihara K, Yamazaki Y, Hara I, Hara E, et al. Reduced immune response to polymeric micelles coating sialic acids. Bioorg Med Chem Lett. 2016;26(20):4976–82.
Abu Lila AS, Uehara Y, Ishida T, Kiwada H. Application of polyglycerol coating to plasmid DNA lipoplex for the evasion of the accelerated blood clearance phenomenon in nucleic acid delivery. J Pharm Sci. 2014;103(2):557–66.
Shiraishi K, Hamano M, Ma H, Kawano K, Maitani Y, Aoshi T, et al. Hydrophobic blocks of PEG-conjugates play a significant role in the accelerated blood clearance (ABC) phenomenon. J Control Release. 2013;165(3):183–90.
This work was supported by the National Natural Science Foundation of China (No. 81973271).
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Li, Z., Gao, X., Yan, X. et al. PEGylated nanoemulsions containing 1,2-distearoyl-sn-glycero-3-phosphoglycerol induced weakened accelerated blood clearance phenomenon. Drug Deliv. and Transl. Res. 12, 2569–2579 (2022). https://doi.org/10.1007/s13346-021-01111-4