In vitro and in vivo characterization of doxorubicin and vincristine coencapsulated within liposomes through use of transition metal ion complexation and pH gradient loading
In vitro and in vivo characterization of doxorubicin and vincristine coencapsulated within liposomes through use of transition metal ion complexation and pH gradient loading
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DOI：
10.1158/1078-0432.ccr-1131-03
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发表时间：
2004-01-15
影响因子：
11.5
通讯作者：
Bally, MB
中科院分区：
文献类型：
--
作者：
Abraham, SA;McKenzie, C;Bally, MB
目的：有机会通过使用药物传递技术来增强药物组合的治疗潜力。本报告总结了使用一种新型脂质体制剂与多柔比星和长春新碱共胶囊获得的数据。选择这些药物的理由部分是由于阿霉素和长春新碱的脂质体制剂作为药物组合的组成部分正在分别进行评估。实验设计：采用两种不同的载药方法将阿霉素和长春新碱共包被脂质体。一种基于锰的药物装载程序，它依赖于药物与过渡金属的络合，被用来包封阿霉素。随后加入离子载体A23187诱导形成pH梯度，促进长春新碱包封。结果：小鼠血浆消除实验表明，注射前药药比[4:1阿霉素：长春新碱（wt:wt比）]在24小时时间点变为20:1，表明脂质体中长春新碱的释放速度比阿霉素更快。在MDA MB-435/LCC6荷瘤小鼠中完成的疗效研究表明，在最大耐受剂量下，共胶囊制剂的治疗效果并不优于长春新碱脂质体。使用Chou和Talalay中位效应原理分析的评估阿霉素和长春新碱联合的体外细胞毒性研究部分解释了这一结果。这些数据清楚地表明，同时添加长春新碱和阿霉素导致明显的拮抗作用。结论：这些结果强调体外药物联合筛选可用于预测共配制药物组合是拮抗还是协同作用。
Purpose: There is an opportunity to augment the therapeutic potential of drug combinations through use of drug delivery technology. This report summarizes data obtained using a novel liposomal formulation with coencapsulated doxorubicin and vincristine. The rationale for selecting these drugs is due in part to the fact that liposomal formulations of doxorubicin and vincristine are being separately evaluated as components of drug combinations.Experimental Design: Doxorubicin and vincristine were coencapsulated into liposomes using two distinct methods of drug loading. A manganese-based drug loading procedure, which relies on drug complexation with a transition metal, was used to encapsulate doxorubicin. Subsequently the ionophore A23187 was added to induce formation of a pH gradient, which promoted vincristine encapsulation.Results: Plasma elimination studies in mice indicated that the drug:drug ratio before injection [4:1 doxorubicin: vincristine (wt:wt ratio)] changed to 20:1 at the 24-h time point, indicative of more rapid release of vincristine from the liposomes than doxorubicin. Efficacy studies completed in MDA MB-435/LCC6 tumor-bearing mice suggested that at the maximum tolerated dose, the coencapsulated formulation was therapeutically no better than liposomal vincristine. This result was explained in part by in vitro cytotoxicity studies evaluating doxorubicin and vincristine combinations analyzed using the Chou and Talalay median effect principle. These data clearly indicated that simultaneous addition of vincristine and doxorubicin resulted in pronounced antagonism.Conclusion: These results emphasize that in vitro drug combination screens can be used to predict whether a coformulated drug combination will act in an antagonistic or synergistic manner.