Dissociable PEGylation alleviates Kupffer cells capture of PEGylated liposomal doxorubicin.

Surface modification by polyethylene glycol (PEG) is valuable to assist clinical translation of lipid-based nanomedicines but suffering "PEG dilemma" due to unavoidable interaction with anti-PEG antibodies. Considering high detection rates of pre-existing anti-PEG antibodies in clinic, it is urgent to enrich PEGylation strategies to resist anti-PEG antibodies and improve drug delivery efficiency. Herein, regulatory effects of different PEGylation strategies on in vivo performance of PEGylated liposomes and related mechanisms were explored. Pharmacokinetics and intrahepatic process of three populations of liposomes, all with the main composition of hydrogenated soybean phosphatidylcholine (HSPC) and cholesterol, and additionally with steady PEGylation by PEG-DSPE, dissociable PEGylation by PEG-DMG, or non-PEGylation, were compared in both normal and anti-PEG antibodies pre-existing mice. PEG-DMG-inserted liposomes exhibited a composite pharmacokinetics profile of the other two liposomes, as plasma concentration obviously decreased due to anti-PEG antibodies within 4 h, and independent of anti-PEG antibodies with time extending. More importantly, PEGylation by PEG-DMG could efficiently alleviate Kupffer cells capture of liposomal doxorubicin, even in anti-PEG antibodies pre-existing mice, following less drug accumulation in hepatocytes, probably due to the synergistic effects of adsorbed proteins containing immune globulin M (IgM), apolipoprotein E (ApoE) and complements. This work unveils the potential of PEGylation by PEG-DMG to alleviate pre-existing anti-PEG antibodies related accelerated blood clearance (ABC) phenomenon and mononuclear phagocyte system (MPS) recognition, and provides a promising strategy to improve in vivo performance of PEGylated nanomedicines.