Saito Ryuta, Krauze Michal T, Noble Charles O, Drummond Daryl C, Kirpotin Dmitri B, Berger Mitchel S, Park John W, Bankiewicz Krystof S
Department of Neurological Surgery, University of California at San Francisco, 1855 Folsom Street, Mission Center Building Room 226, San Francisco, CA 94103, USA.
Neuro Oncol. 2006 Jul;8(3):205-14. doi: 10.1215/15228517-2006-001. Epub 2006 May 24.
Treatment of malignant gliomas represents one of the most formidable challenges in oncology. The combination of surgery, radiation, and chemotherapy yields median survivals of less than one year. Here we demonstrate the use of a minimally invasive surgical technique, convection-enhanced delivery (CED), for local administration of a novel nanoparticle liposome containing topotecan. CED of this liposomal topotecan (Ls-TPT) resulted in extended brain tissue retention (t1/2 = 1.5 days), whereas free topotecan was rapidly cleared (t1/2 = 0.1 days) after CED. The favorable pharmacokinetic profile of extended topotecan release for about seven days, along with biodistribution featuring perivascular accumulation of the nanoparticles, provided, in addition to the known topoisomerase I inhibition, an effective antiangiogenic therapy. In the rat intracranial U87MG tumor model, vascular targeting of Ls-TPT with CED was associated with reductions in laminin expression and vascular density compared to free topotecan or control treatments. A single CED treatment on day 7 showed that free topotecan conferred no survival benefit versus control. However, Ls-TPT produced a significant (P = 0.0002) survival benefit, with six of seven complete cures. Larger U87MG tumors, where CED of Ls-TPT on day 12 resulted in one of six cures, indicated the necessity to cover the entire tumor with the infused therapeutic agent. CED of Ls-TPT was also efficacious in the intracranial U251MG tumor model (P = 0.0005 versus control). We conclude that the combination of a novel nanoparticle Ls-TPT and CED administration was very effective in treating experimental brain tumors.
恶性胶质瘤的治疗是肿瘤学中最严峻的挑战之一。手术、放疗和化疗联合使用的中位生存期不足一年。在此，我们展示了一种微创外科技术——对流增强递送（CED），用于局部给予含拓扑替康的新型纳米颗粒脂质体。这种脂质体拓扑替康（Ls - TPT）经CED给药后，脑组织中的保留时间延长（t1/2 = 1.5天），而游离拓扑替康在CED给药后迅速清除（t1/2 = 0.1天）。拓扑替康延长释放约七天的良好药代动力学特征，以及纳米颗粒在血管周围蓄积的生物分布特点，除了已知的拓扑异构酶I抑制作用外，还提供了一种有效的抗血管生成疗法。在大鼠颅内U87MG肿瘤模型中，与游离拓扑替康或对照治疗相比，CED靶向Ls - TPT与层粘连蛋白表达和血管密度降低有关。在第7天进行单次CED治疗显示，游离拓扑替康与对照相比未带来生存获益。然而，Ls - TPT产生了显著的（P = 0.0002）生存获益，七只大鼠中有六只完全治愈。更大的U87MG肿瘤，在第12天对其进行Ls - TPT的CED治疗，六只大鼠中有一只治愈，这表明需要用注入的治疗剂覆盖整个肿瘤。Ls - TPT的CED在颅内U251MG肿瘤模型中也有效（与对照相比，P = 0.0005）。我们得出结论，新型纳米颗粒Ls - TPT与CED给药相结合在治疗实验性脑肿瘤方面非常有效。
