Transition metal-mediated liposomal encapsulation of irinotecan (CPT-11) stabilizes the drug in the therapeutically active lactone conformation
Transition metal-mediated liposomal encapsulation of irinotecan (CPT-11) stabilizes the drug in the therapeutically active lactone conformation
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DOI：
10.1007/s11095-006-9111-5
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发表时间：
2006-12-01
影响因子：
3.7
通讯作者：
Bally, Marcel
中科院分区：
文献类型：
--
作者：
Ramsay, Euan;Alnajim, Jehan;Bally, Marcel
目的.确定包埋的过渡金属是否可以介导抗癌药物伊立替康活性包封到预先形成的脂质体中。此外，为了确定金属络合可以将脂质体伊立替康稳定在治疗活性内酯构象。将伊立替康加入到在CuSO 4、ZnSO 4、MnSO 4或CoSO 4溶液中制备的预先形成的1，2-二硬脂酰-sn-甘油-磷酸胆碱/胆固醇（DSPC/chol）脂质体中，并随时间测定药物包封率。评价了跨膜pH梯度和内部pH的作用。采用薄层色谱法和高效液相色谱法考察药物的稳定性，低温透射电镜观察脂质体的形态。将伊立替康快速有效地加载到在非缓冲（类似于pH 3.5）300 mM CuSO 4或ZnSO 4中制备的预成型脂质体中。对于含Cu脂质体，结果表明当内部pH值和外部pH值匹配时发生伊立替康负载;然而，添加尼日利亚菌素以破坏任何残留跨膜pH梯度抑制伊立替康负载。90%以上的包封药物以其活性内酯形式存在，冷冻-TEM分析表明囊泡内有深色的电子致密点。由于金属-药物络合，伊立替康以活性内酯构象稳定包埋在预成型含铜脂质体中。
Purpose. To determine whether entrapped transition metals could mediate the active encapsulation of the anticancer drug irinotecan into preformed liposomes. Further, to establish that metal complexation could stabilize liposomal irinotecan in the therapeutically active lactone conformation.Materials and Methods. Irinotecan was added to preformed 1,2-distearoyl-sn-glycero-phosphocholine/cholesterol (DSPC/chol) liposomes prepared in CuSO4, ZnSO4, MnSO4, or CoSO4 solutions, and drug encapsulation was determined over time. The roles of the transmembrane pH gradient and internal pH were evaluated. TLC and HPLC were used to monitor drug stability and liposome morphology was assessed by cryo-TEM.Results. Irinotecan was rapidly and efficiently loaded into preformed liposomes prepared in unbuffered (similar to pH 3.5) 300 mM CuSO4 or ZnSO4. For Cu-containing liposomes, results suggested that irinotecan loading occurred when the interior pH and the exterior pH were matched; however, addition of nigericin to collapse any residual transmembrane pH gradient inhibited irinotecan loading. Greater than 90% of the encapsulated drug was in its active lactone form and cryo-TEM analysis indicated dark intravesicular electron-dense spots.Conclusion. Irinotecan is stably entrapped in the active lactone conformation within preformed copper-containing liposomes as a result of metal-drug complexation.