治疗转移性肺癌的肺吸入羟基喜树碱脂质体粉雾剂研究

Pulmonary delivery of liposomal hydroxycamptothecin dry powder inhalers for metastatic lung cancer

目的制备适合肺吸入给药的羟基喜树碱阳离子脂质体粉雾剂(CLHD),用于小鼠转移性肺癌的治疗。方法采用薄膜分散法制备羟基喜树碱脂质体(LH),并通过正交设计优化脂质体的处方,加入甘露醇冻干后得到粉雾剂。通过尾静脉注射荧光标记的4T1细胞建立小鼠转移性肺癌模型,考察CLHD经气管和静脉注射给药后对转移性肺癌的疗效。结果羟基喜树碱阳离子脂质体的最优处方为大豆磷脂与胆固醇的摩尔比为4∶1,磷脂与羟基喜树碱(HCPT)的摩尔比为10∶1,PBS与甲醇体积比为3∶1;包封率为89.71%。CLHD的空气动力学中位粒径为4.85μm,体外有效部位沉积率较高,可达19.58%。小鼠活体成像荧光强度、肺组织外观及病理学指标证明,CLHD肺部给药对转移性肺癌有显著治疗作用,效果优于静脉注射给药。结论CLHD有望用于转移性肺癌的临床治疗。

Objective To prepare inhalable cationic liposomal hydroxycamptothecin(LH)dry powder inhalers(CLHDs for treatment of metastatic lung cancer of mice.Methods LH was prepared using the film method.The optimal formulation of LH was obtained by the orthogonal experimental design.LH was mixed with mannitol and freeze-dried to CLHDs.Metastatic lung cancer mouse models were established following intravenous(i.v.)injection of luciferase-tagged 4 T1 cells.Effects of intratracheal(i.t.)CLHDs and i.v.injection of CLHDs on the cancer models were explored.Results As the optimal formulation of LH,the molar ratio of soybean phospholipids to cholesterol was 4∶1,that of soybean phospholipids to hydroxycamptothecin was 10∶1,the volume ratio of PBS to methyl alcohol was 3∶1,and the rate of encapsulation was 89.71%.The CLHDs had an aerodynamic median diameter of 4.85μm and the in vitro deposition test showed that the respirable fraction was 19.58%.CLHDs i.t.had a much higher anti-metastatic lung cancer effect than CLHDs i.v.according to in vivo fluorescence imaging,appearance and pathology of lung tissues.Conclusion CLHDs are promising medications for metastatic lung cancer.