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

• Published in: International journal of pharmaceutics 2008-10, Vol.362 (1), p.60-66
• Main Authors: Li, ChunLei, Cui, JingXia, Wang, CaiXia, Wang, JinXu, Li, YanHui, Zhang, Lan, Zhang, Li, Guo, WenMin, Wang, YongLi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Antitumor efficacy; Cell Line, Tumor; Drug Compounding; Drug release; Drug Screening Assays, Antitumor; Lipid composition; Lipids - chemistry; Liposomes; Male; Mice; Mice, Inbred BALB C; Mitoxantrone; Mitoxantrone - administration & dosage; Mitoxantrone - chemistry; Mitoxantrone - pharmacokinetics; Mitoxantrone - therapeutic use; Mitoxantrone - toxicity; Neoplasm Transplantation; Neoplasms - drug therapy; Phosphatidylcholines - chemistry; Polyethylene glycol grafting density; Polyethylene Glycols - chemistry; Solubility; Tissue Distribution; Toxicity; Toxicity Tests, Acute
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2008.06.008

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 T m of PCs, and reduced PEG polymer coverage. In circulation, the trend towards increased circulation time as T m 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.