TY - JOUR
T1 - Premature Drug Release from Polyethylene Glycol (PEG)-Coated Liposomal Doxorubicin via Formation of the Membrane Attack Complex
AU - Chen, Even
AU - Chen, Bing Mae
AU - Su, Yu Cheng
AU - Chang, Yuan Chih
AU - Cheng, Tian Lu
AU - Barenholz, Yechezekel
AU - Roffler, Steve R.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - anti-PEG antibody
KW - complement
KW - drug release
KW - membrane attack complex
KW - PEG-coated liposomal doxorubicin
KW - PEGylated liposomal doxorubicin
UR - http://www.scopus.com/inward/record.url?scp=85081697194&partnerID=8YFLogxK
U2 - 10.1021/acsnano.9b07218
DO - 10.1021/acsnano.9b07218
M3 - Article
C2 - 32142248
AN - SCOPUS:85081697194
JO - ACS Nano
JF - ACS Nano
SN - 1936-0851
ER -