Dexamethasone ameliorates dermatologic adverse effects of PEGylated liposomal doxorubicin

While PEGylated liposomal doxorubicin (PLD) reduces systemic toxicity compared with free doxorubicin, its accumulation in the skin leads to severe, dose-limiting cutaneous toxicities, particularly hand-foot syndrome. Complement activation has been identified as a critical driver of neutrophil uptake of liposomes, which subsequently mediates its trans-endothelial transport into the skin. Dexamethasone, a glucocorticoid routinely co-administered with PLD to prevent infusion reactions, exhibits complement-inhibitory activity and may therefore mitigate PLD-induced cutaneous toxicity. Here, we demonstrate that dexamethasone markedly reduces neutrophil uptake of PLD, leading to decreased cutaneous accumulation and toxicity in mice and rats, without compromising antitumor efficacy in 4T1 tumor-bearing mice. Consistently, retrospective analysis of 171 cancer patients receiving PLD revealed a dose-dependent alleviation of cutaneous toxicities by glucocorticoids. Together, these results confirm complement-driven, neutrophil-mediated transport as an important mechanism of PLD skin accumulation and identify dexamethasone as a clinically feasible strategy to alleviate PLD-induced cutaneous toxicity.