Nigericin-mediated liposome loading of topotecan: Is nigericin a potential drug release regulator?

被引:10
|
作者
Cui, JingXia [2 ]
Li, ChunLei [1 ,3 ]
Wang, CaiXia [1 ,3 ]
Li, YanHui [1 ,3 ]
Zhang, Lan [1 ,3 ]
Zhang, Li [1 ,3 ]
Xiu, Xian [1 ,3 ]
Li, YongFeng [1 ,3 ]
Wei, Na [1 ,3 ]
机构
[1] CSPC ZhongQi Pharmaceut Technol Shijiazhuang Co L, Shijiazhuang 050051, Hebei Province, Peoples R China
[2] Hebei Med Univ, Sch Pharm, Shijiazhuang 050017, Hebei Province, Peoples R China
[3] Hebei Pharmaceut Engn & Technol Res Ctr, Shijiazhuang 050051, Hebei Province, Peoples R China
关键词
Liposomes; Topotecan; Nigericin; Drug release; Active loading; Toxicity; Efficacy; Pharmacokinetics; LARGE UNILAMELLAR VESICLES; TRANSMEMBRANE PH GRADIENTS; XENOGRAFT MODELS; IN-VITRO; VINCRISTINE; ENCAPSULATION; DOXORUBICIN; RETENTION; COMPLEXATION; FORMULATIONS;
D O I
10.1016/j.ijpharm.2010.07.050
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Topotecan was loaded into large unilamellar vesicles using nigericin-generated pH gradient or with triethylammonium (TA) ion gradient. Despite that in both loading methods, the encapsulated counter ion was 5-sulfosalicylate (5ssa), the resultant formulations exhibited distinct properties. In NaCl-containing release buffer, vesicles prepared with nigericin/Na+ system could release topotecan at a faster rate than 5ssa-TA vesicles, whereas in the absence of Na+, there was no difference in the drug release kinetics. In plasma, both formulations could prolong the circulation halftime of topotecan, but 5ssa-TA vesicles were more able to stabilize the encapsulated topotecan, as evidenced by the increased t(1/2) and decreased conversion of lactone to carboxylate form. However, the improved drug retention did not mean the elevated safety and efficacy. In L1210 ascitic tumor model, the administration of 5ssa-TA vesicles at 10 mg/kg induced the early death of similar to 60% mice at 6-7 days. In contrast, the treatment with nigericin/Na+ vesicles at the same dose level resulted in a mean survival time of similar to 18.0 days, similar to 1.38-fold of that of free topotecan. In addition, the formulation was safer than free topotecan. The results indicated that nigericin could be used as release regulator to optimize drug release kinetics, resulting in safe and efficacious liposome-based topotecan formulation. The results were promising since no liposome topotecan formulations with reduced toxicity were reported. (C) 2010 Elsevier B.V. All rights reserved.
引用
收藏
页码:31 / 36
页数:6
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