Accelerated blood clearance of PEGylated nanoparticles induced by PEG-based pharmaceutical excipients

• Published in: Journal of controlled release 2023-11, Vol.363, p.12-26
• Main Authors: Miao, Guifeng, He, Yuejian, Lai, Keren, Zhao, Yan, He, Peiyi, Tan, Guozhu, Wang, Xiaorui
• Format: Article
• Language: English
• Subjects: ABC effect; Anti-PEG antibodies; PEGylated nanoparticles; Pharmaceutical excipients; Polyethylene glycol (PEG)
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2023.09.003

PEGylated nanomedicines have been extensively developed and applied to cancer therapy. However, the antitumor efficacy of these nanoparticles is hampered by the accelerated blood clearance (ABC) effect caused by anti-PEG antibodies in vivo. There is still limited understanding about the cause of pre-existing anti-PEG antibodies in the human body. Herein, we discovered that PEG-based pharmaceutical excipients, commonly used in clinical and daily settings, could induce anti-PEG antibodies in vivo and lead to considerable potential clinical impacts on pharmacokinetics and pharmacodynamics of PEGylated nanoparticles. Specifically, we investigated the ability of poloxamer 188 (F68) and poloxamer 407 (F127), the two most frequently used PEG-based pharmaceutical excipients, to elicit the production of anti-PEG antibodies and influence the pharmacokinetics of PEGylated nanoparticles, with PEGylated liposome nanoparticles (L-NPs) as a model. Anti-PEG IgG and IgM levels were significantly boosted 3.8- and 32.2-fold, respectively, after pre-injection with F68, leading to rapid clearance of subsequently injected L-NPs from circulation due to the capture by neutrophils and monocytes. However, pre-injection of F127 did not induce the production of anti-PEG IgG, although there was a 7.7-fold increase in IgM level, which resulted in minimal effect on circulation time of L-NPs. Furthermore, the potential clinical impacts of F68 and F127 were further inspected for PEGylated liposomal doxorubicin (PLD). It was found that administering F68 prior to treatment led to over a one-third decrease in the antitumor effectiveness of PLD, while F127 had a negligible impact. Our study elucidates the mechanism by which PEG-based pharmaceutical excipients influence the effectiveness of PEGylated nanomedicines. It also highlights the significance of considering the potential for an ABC effect induced by PEG-based pharmaceutical excipients in patients. [Display omitted] •The regular utilization of PEG-based pharmaceutical excipients may be a potential source of anti-PEG antibodies in healthy individuals.•PEG-based excipients can induce the production of anti-PEG Igs, leading to rapid clearance of subsequently injected PEGylated nanoparticles.•PEG-based pharmaceutical excipients differed in their potential to trigger the ABC effect.