posted on 2020-03-06, 16:00authored byEven Chen, Bing-Mae Chen, Yu-Cheng Su, Yuan-Chih Chang, Tian-Lu Cheng, Yechezekel Barenholz, Steve R. Roffler
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.