Antibodies against Poly(ethylene glycol) Activate Innate Immune Cells and Induce Hypersensitivity Reactions to PEGylated Nanomedicines.

Nanomedicines and macromolecular drugs can induce hypersensitivity reactions (HSRs) with symptoms ranging from flushing and breathing difficulties to hypothermia, hypotension, and death in the most severe cases. Because many normal individuals have pre-existing antibodies that bind to poly(ethylene glycol) (PEG), which is often present on the surface of nanomedicines and macromolecular drugs, we examined if and how anti-PEG antibodies induce HSRs to PEGylated liposomal doxorubicin (PLD). Anti-PEG IgG but not anti-PEG IgM induced symptoms of HSRs including hypothermia, altered lung function, and hypotension after PLD administration in C57BL/6 and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Hypothermia was significantly reduced by blocking FcγRII/III, by depleting basophils, monocytes, neutrophils, or mast cells, and by inhibiting secretion of histamine and platelet-activating factor. Anti-PEG IgG also induced hypothermia in mice after administration of other PEGylated liposomes, nanoparticles, or proteins. Humanized anti-PEG IgG promoted binding of PEGylated nanoparticles to human immune cells and induced secretion of histamine from human basophils in the presence of PLD. Anti-PEG IgE could also induce hypersensitivity reactions in mice after administration of PLD. Our results demonstrate an important role for IgG antibodies in induction of HSRs to PEGylated nanomedicines through interaction with Fcγ receptors on innate immune cells and provide a deeper understanding of HSRs to PEGylated nanoparticles and macromolecular drugs that may facilitate development of safer nanomedicines.

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

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.

Liposomes enhance bioremediation of oil-contaminated soil.

Liposomes (composed of soy phosphatides) in the form of small unilamellar vesicles (SUV), when added to soil contaminated by crude oil, accelerate bioremediation. After three weeks incubation at 30 degrees C, using soil experimentally contaminated (with 10,000 ppm crude oil), level of bioremediation increased from 40% without SUV to 75% with SUV (0.1 wt% phospholipids per dry weight soil). Similarly, for accidentally contaminated soil (with approximately 17,000 ppm crude oil), addition of 0.1 wt% SUV to the soil increased the bioremediation level from 55 to 80%. The enhancing effect of liposomes is explained by two interrelated phenomena: a large increase both in total bacteria number and in diversity of bacterial species in the soil. Comparison after four weeks revealed 21 bacterial species in the presence of liposomes (many being oil-degrading bacterial species) and only nine species in the absence of liposomes. Both effects may be related to the physical effects of liposome phospholipids, which modify the crude oil by wetting it, thereby making it more accessible to the microorganisms. In addition, liposome phospholipids serve as phosphate and nitrogen sources for the bacteria.