Menaquinone-7 co-loading prevents mitoxantrone liposome-induced hand-foot syndrome and systemic toxicity while maintaining antitumor activity

PEGylation prolongs the circulation of liposomal formulations but also leads to significant and persistent drug accumulation in the skin, particularly in the palms and soles. For instance, PEGylated liposomal doxorubicin is associated with hand-foot syndrome (HFS), a dose-limiting cutaneous toxicity. Mitoxantrone (MIT), another cytotoxic anthracenedione, shares similar physicochemical properties; however, no studies have reported its association with HFS to date. This study first demonstrated that PEGylated mitoxantrone liposomes induce HFS symptoms and established a reliable rat model recapitulating the clinical features of HFS. Given the anti-inflammatory activity and multi-pathway antitumor potential of menaquinone-7 (MK7), this compound was incorporated into the lipid bilayer of MIT liposomes to construct MK7/MIT co-loaded liposomes. This co-loaded formulation not only prevented the onset of HFS but also reduced MIT-induced systemic toxicity while maintaining antitumor efficacy. To directly address HFS induced by MIT liposomes and to explore the preventive effects of other vitamin K homologs, three vitamin K liposomes were prepared. All three vitamin K liposomes alleviated HFS and mitigated MIT-induced toxicities. This study is expected to provide novel theoretical insights into resolving the skin toxicity dilemma of PEGylated mitoxantrone liposomes in clinical application and achieving safer cancer chemotherapy.