Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of poly-L-glutamic acid (PGA) and cationic liposome/siRNA complex (cationic lipoplex). In this study, we examined...Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of poly-L-glutamic acid (PGA) and cationic liposome/siRNA complex (cationic lipoplex). In this study, we examined the effects of the charge ratio (+/-) of cationic liposome/siRNA, molecular weight of PGA and cationic lipid of cationic liposome on the biodistribution of siRNA after sequential injection of PGA plus cationic lipoplex. When 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (Chol) lipoplex was intravenously injected into mice, the accumulation of siRNA was mainly observed in the lungs. In contrast, when DOTAP/Chol lipoplex was intravenously injected at 1 min after intravenous injection of PGA, siRNA was largely accumulated in the liver. The charge ratio (+/-) of DOTAP/Chol liposome/siRNA did not affect the biodistribution of siRNA after sequential injection. As regards the molecular weight of PGA, the accumulation of siRNA was observed mainly in the liver after the sequential injection of PGA of 20.5, 38, 64 or 200 kDa plus DOTAP/Chol lipoplex. Furthermore, to examine the effect of cationic lipid of cationic liposome on the biodistribution of siRNA, we prepared other cationic liposomes composed of 1,2-di-O-octadecenyl-3-trimethylammonium propane chloride (DOTMA)/Chol, dimethyldioctade-cylammonium bromide (DDAB)/Chol and O,O’-ditetradecanoyl-N-(α-trimethylammonioacetyl)di-ethanolamine chloride (DC-6-14)/Chol. For the cationic liposomes, the accumulation of siRNA was observed mainly in the liver when their cationic lipoplexes were sequentially injected after injection of PGA into mice. From these findings, sequential injection of PGA plus cationic lipoplex could deliver siRNA efficiently into the liver regardless of the charge ratio (+/-) of lipoplex, lengths of PGA and cationic lipid of liposome.展开更多
文摘目的比较紫杉醇脂质体与紫杉醇注射液在大鼠体内的血药浓度及相关药动学参数。方法大鼠经尾静脉注射紫杉醇注射液或紫杉醇脂质体注射液12 mg/kg后,采用HPLC法测定大鼠体内的血药浓度,得出药-时曲线图及采用3p87药动学软件得到相关药动学参数;同时采用SPSS17.0统计软件进行t检验。结果紫杉醇注射液及紫杉醇脂质体在大鼠血浆样品中的浓度分别为(0.21±0.11)、(48.12±9.42)C·mg-1·L-1,差异具有统计学意义(t=12.457,P<0.001);紫杉醇脂质体药-时曲线下面积(AUC)较紫杉醇注射液大(17.578±2.428 vs 10.422±2.784,t=4.745,P<0.001),清除率(Cl)较紫杉醇注射液慢〔(7.4±1.1)vs(1.3±2.5)×10-4L,t=5.471,P<0.001〕,表观分布容积(Vc)较紫杉醇注射液小〔(1.523±1.882)×10-3L vs(5.314±1.211)×10-3L,t=4.059,P<0.002〕。结论紫杉醇脂质体与紫杉醇注射液在大鼠体内药动学显著不同,不仅能使药物在体内的浓度维持较长时间,而且使药物更好的聚集于肿瘤靶组织,从而增加治疗疗效,减少毒副作用。
文摘Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of poly-L-glutamic acid (PGA) and cationic liposome/siRNA complex (cationic lipoplex). In this study, we examined the effects of the charge ratio (+/-) of cationic liposome/siRNA, molecular weight of PGA and cationic lipid of cationic liposome on the biodistribution of siRNA after sequential injection of PGA plus cationic lipoplex. When 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (Chol) lipoplex was intravenously injected into mice, the accumulation of siRNA was mainly observed in the lungs. In contrast, when DOTAP/Chol lipoplex was intravenously injected at 1 min after intravenous injection of PGA, siRNA was largely accumulated in the liver. The charge ratio (+/-) of DOTAP/Chol liposome/siRNA did not affect the biodistribution of siRNA after sequential injection. As regards the molecular weight of PGA, the accumulation of siRNA was observed mainly in the liver after the sequential injection of PGA of 20.5, 38, 64 or 200 kDa plus DOTAP/Chol lipoplex. Furthermore, to examine the effect of cationic lipid of cationic liposome on the biodistribution of siRNA, we prepared other cationic liposomes composed of 1,2-di-O-octadecenyl-3-trimethylammonium propane chloride (DOTMA)/Chol, dimethyldioctade-cylammonium bromide (DDAB)/Chol and O,O’-ditetradecanoyl-N-(α-trimethylammonioacetyl)di-ethanolamine chloride (DC-6-14)/Chol. For the cationic liposomes, the accumulation of siRNA was observed mainly in the liver when their cationic lipoplexes were sequentially injected after injection of PGA into mice. From these findings, sequential injection of PGA plus cationic lipoplex could deliver siRNA efficiently into the liver regardless of the charge ratio (+/-) of lipoplex, lengths of PGA and cationic lipid of liposome.
