Poly(ethylene Glycol) Densities Determine the Mechanism of the Accelerated Blood Clearance of PEGylated Liposomes.

Polyethylene glycol (PEG) is used to graft liposomes with different densities to enhance their colloidal stability or blood circulation time, such as 0.3 mol % for commercial Onivyde and 5 mol % for DOXIL. However, the influence of PEG density on the mechanism of the accelerated blood clearance (ABC) of PEGylated liposomes remains unclear. In this study, we comparatively investigate the ABC phenomenon of liposomes modified with 0.3% and 5% molar ratios of PEG, and found that they displayed completely different mechanisms induced by anti-PEG antibodies. The ABC of liposomes grafted with 0.3 mol % PEG was induced by high-affinity anti-PEG antibodies, whereas the ABC of liposomes grafted with 5 mol % PEG was caused by both high and low-affinity anti-PEG antibodies. Free PEG can bind to high-affinity anti-PEG antibodies but not to low-affinity antibodies. Therefore, preinjecting a low dose of PEG completely inhibits the ABC of 0.3 mol % PEGylated liposomes while only partially decreasing the ABC of 5 mol % PEGylated liposomes in the PEG-immunized rats. These results suggest that the interfacial PEG density determines the mechanism of the ABC phenomenon of PEGylated liposomes, and the ABC of Onivyde can be readily inhibited by removing high-affinity anti-PEG antibodies in blood through preinjection of a low dose of PEG.