Anti-PEG antibodies drive contrasting liposome skin toxicity across species

This new article publication from Acta Pharmaceutica Sinica B discusses how anti-polyethylene glycol antibodies affect the movement of stealth liposomes from blood into skin, revealing contrasting distribution and toxicity patterns in mice and rats.

Polyethylene glycol (PEG)-coated, or stealth, liposomes are widely used drug carriers, but their interactions with the immune system can influence where encapsulated medicines accumulate. For liposomal doxorubicin, skin exposure can contribute to adverse effects such as hand-foot syndrome. The authors of this article investigated how anti-PEG antibodies alter liposome transport and skin toxicity across species. Using antibody-stimulated and control mice and rats, the researchers combined liposome tracking, immune-cell analysis, tissue imaging, pharmacokinetic modeling, and toxicity assessments. Anti-PEG IgM antibodies enhanced uptake of stealth liposomes by neutrophils, immune cells capable of carrying the particles from the circulation into skin. However, the overall outcome differed markedly between species.

In mice, relatively limited complement activity allowed antibody-bound liposomes to remain available for neutrophil-mediated skin delivery, increasing cutaneous accumulation and worsening skin toxicity after liposomal doxorubicin administration. In rats, stronger complement activation and uptake by macrophages in the liver and spleen accelerated systemic clearance, reducing the amount of liposomes reaching the skin. The researchers' plasma-skin model supported the competing contributions of transport into skin, local clearance, and elimination from the circulation. Additional experiments varying antibody levels indicated that antibody concentration influenced the magnitude of the response but did not explain the opposing distribution patterns between species. These findings highlight the combined roles of antibodies, complement proteins, and phagocytic cells in determining the fate of liposomal medicines.

The research provides a mechanistic basis for considering immune-system differences when selecting animal models and interpreting preclinical skin-toxicity results. Further clinical investigation is needed to establish how these mechanisms affect individual patients and to guide approaches for predicting and reducing liposomal toxicity.