Premature Drug Release from Polyethylene Glycol (PEG)-Coated Liposomal Doxorubicin via Formation of the Membrane Attack Complex

ACS Nano
Even ChenSteve R Roffler

Abstract

Anti-polyethylene glycol (PEG) antibodies are present in many healthy individuals as well as in patients receiving polyethylene glycol-functionalized drugs. Antibodies against PEG-coated nanocarriers can accelerate their clearance, but their impact on nanodrug properties including nanocarrier integrity is unclear. Here, we show that anti-PEG IgG and IgM antibodies bind to PEG molecules on the surface of PEG-coated liposomal doxorubicin (Doxil, Doxisome, LC-101, and Lipo-Dox), resulting in complement activation, formation of the membrane attack complex (C5b-9) in the liposomal membrane, and rapid release of encapsulated doxorubicin from the liposomes. Drug release depended on both classical and alternative pathways of complement activation. Doxorubicin release of up to 40% was also observed in rats treated with anti-PEG IgG and PEG-coated liposomal doxorubicin. Our results demonstrate that anti-PEG antibodies can disrupt the membrane integrity of PEG-coated liposomal doxorubicin through activation of complement, which may alter therapeutic efficacy and safety in patients with high levels of pre-existing antibodies against PEG.

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Citations

Aug 26, 2020·Annual Review of Pharmacology and Toxicology·Wen YangStefan Wilhelm
Jan 1, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Zui ZhangChangyou Zhan
Apr 4, 2021·Macromolecular Bioscience·Xin LiXikuang Yao
Aug 8, 2021·Acta Biomaterialia·Natalia OnishchenkoElena Vodovozova

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