Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts
Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts
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DOI：
10.1215/15228517-2007-019
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发表时间：
2007-10-01
期刊：
影响因子：
15.9
通讯作者：
Bankiewicz, Krystof S.
中科院分区：
文献类型：
--
作者：
Krauze, Michal T.;Noble, Charles O.;Bankiewicz, Krystof S.
我们之前已经证明，对流增强递送(CED)包裹化疗药物的高度稳定的纳米颗粒/脂质体对颅内啮齿动物脑瘤移植瘤是有效的。在这项研究中，我们评价了一种新开发的含有拓扑异构酶I抑制剂CPT-11(纳米脂质体CPT-11[NLS-CPT-11])的纳米粒/脂质体与含有拓扑异构酶II抑制剂阿霉素的聚乙二醇化脂质体阿霉素(Doxil)的组合。在一次CED应用后，这两种药物在中枢神经系统中都可以检测到超过36天。NLS-CPT-11和Doxil的组织半衰期分别为16.7天和10.9天。两种药物联合使用在体外产生了协同的细胞毒性。在体内U251 MG和U87 MG鼠脑内移植模型中，联合用药的CED也比单独使用任何一种药物更有效。对这一方法中涉及的参数的分析表明，组织药代动力学、肿瘤显微解剖和药物的生化相互作用都有助于观察到的治疗效果。这些发现对基于CED的脑肿瘤治疗的进一步临床应用具有重要意义。
We have previously shown that convection-enhanced delivery (CED) of highly stable nanoparticle/liposome agents encapsulating chemotherapeutic drugs is effective against intracranial rodent brain tumor xenografts. In this study, we have evaluated the combination of a newly developed nanoparticle/ liposome containing the topoisomerase I inhibitor CPT-11 (nanoliposomal CPT-11 [nLs-CPT-11]), and PEGylated liposomal doxorubicin (Doxil) containing the topoisomerase II inhibitor doxorubicin. Both drugs were detectable in the CNS for more than 36 days after a single CED application. Tissue half-life was 16.7 days for nLs-CPT-11 and 10.9 days for Doxil. The combination of the two agents produced synergistic cytotoxicity in vitro. In vivo in U251MG and U87MG intracranial rodent xenograft models, CED of the combination was also more efficacious than either agent used singly. Analysis of the parameters involved in this approach indicated that tissue pharmacokinetics, tumor microanatomy, and biochemical interactions of the drugs all contributed to the therapeutic efficacy observed. These findings have implications for further clinical applications of CED-based treatment of brain tumors.