標題: Premature Drug Release from Polyethylene Glycol (PEG)-Coated Liposomal Doxorubicin via Formation of the Membrane Attack Complex
作者: Chen, Even
Chen, Bing-Mae
Su, Yu-Cheng
Chang, Yuan-Chih
Cheng, Tian-Lu
Barenholz, Yechezekel
Roffler, Steve R.
生物科技學系
Department of Biological Science and Technology
關鍵字: anti-PEG antibody;PEG-coated liposomal doxorubicin;PEGylated liposomal doxorubicin;complement;membrane attack complex;drug release
公開日期: 28-Jul-2020
摘要: 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 (C51/-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.
URI: http://dx.doi.org/10.1021/acsnano.9b07218
http://hdl.handle.net/11536/155437
ISSN: 1936-0851
DOI: 10.1021/acsnano.9b07218
期刊: ACS NANO
Volume: 14
Issue: 7
起始頁: 7808
結束頁: 7822
Appears in Collections:Articles