Effects of anti-PEG antibodies on extravascular transport of stealth liposome: A study on interspecies difference

Cutaneous toxicity of stealth liposomal doxorubicin (sLip/DOX) has been attributed to the phagocytosis and extravascular transport of the liposomal carrier into skin by circulating neutrophils, which depended on the complement-mediated opsonization. As potent triggers of complement activation, anti-polyethylene glycol (PEG) antibodies may critically influence the cutaneous accumulation of liposomes, which has not been systematically investigated. Moreover, interspecies variability complicates the preclinical evaluation and prediction of liposomal toxicity. To bridge this gap, the present work evaluated the effects of anti-PEG antibody on the extravascular transport of stealth liposome (sLip) from an interspecies perspective. The study also investigated how anti-PEG antibody-mediated complement activation differentially shapes the cutaneous distribution dynamics and spatial accumulation patterns of liposomal drugs across species. Strikingly, mice exhibited increased skin accumulation and toxicity in the presence of anti-PEG antibody, whereas rats showed reduced cutaneous exposure due to predominant hepatic-splenic clearance. Collectively, our findings suggested that interspecies physiological variabilities determine the in vivo fate of sLip and provided mechanistic insights for predicting and mitigating liposomal toxicities in translational settings. Anti-PEG IgM activates complement, driving species-dependent distribution of stealth liposomes: skin accumulation in mice but sequestration by the mononuclear phagocyte system in rats.