Lipid composition and grafted PEG affect in vivo activity of liposomal mitoxantrone

Mitoxantrone was encapsulated into pegylated SUVs using ammonium sulfate gradient method. Four formulations (LM-s, LM-p, LM-m and LM-m-L) were prepared, which were made from different PCs and exhibited different PEG grafting density. In vitro release studies revealed that drug release rate increased with decreased Tm of PCs, and reduced PEG polymer coverage. In circulation, the trend towards increased circulation time as Tm of PCs and PEG lipid content are elevated is observed. However, it was found that the order of toxicity in balb/c mice was Lm-s < LM-p < LM-m-L < LM-m. Biodistribution studies revealed that the accumulation of LM-s into tumor was ∼12 times as large as that of free MIT. In s-180 tumor model, LM-s exhibited significant antineoplastic effects. Following the injection of LM-s (4 mg/kg), tumor growth was considerably inhibited, resulting in a tumor inhibition ratio of ∼92%. In contrast, the treatment with free MIT exhibited almost no antitumor efficacy. In conclusion, PC composition and PEG grafting density could exert influences on the biological activity of liposomal MIT; and encapsulation of MIT into HSPC/chol SUVs with high PEG grafting density could considerably improve the therapeutic index of MIT.