Dexamethasone-loaded block copolymer nanoparticles induce leukemia cell death and enhance therapeutic efficacy: a novel application in pediatric nanomedicine.
Dexamethasone-loaded block copolymer nanoparticles induce leukemia cell death and enhance therapeutic efficacy: a novel application in pediatric nanomedicine.
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地塞米松的块共聚物纳米颗粒会诱导白血病细胞死亡并增强治疗功效：一种新的小儿纳米医学应用。
DOI：
10.1021/mp300350e
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发表时间：
2013-06-03
影响因子：
4.9
通讯作者：
Rajasekaran AK
中科院分区：
文献类型：
--
作者：
Krishnan V;Xu X;Barwe SP;Yang X;Czymmek K;Waldman SA;Mason RW;Jia X;Rajasekaran AK
纳米技术方法在用较低剂量的化疗药物提高治疗效果方面具有巨大的潜力。基于纳米颗粒的药物递送方法在儿童白血病中的开发不足。地塞米松（Dex）是治疗儿童白血病最常用的化疗药物之一。在这项研究中，我们将Dex封装在聚合物纳米颗粒中，并在体外和体内验证其抗白血病的潜力。由两亲性嵌段共聚物聚乙二醇（PEG）和聚己内酯（PCL）组装了平均粒径为110 nm的纳米粒子（NPs）。空白纳米粒对体外培养细胞和小鼠体内均无毒性。将Dex包封到纳米颗粒（Dex-NP）中不会损害药物的生物活性。Dex-NPs诱导糖皮质激素磷酸化，并在白血病细胞中显示出与游离Dex相似的细胞毒性。使用荧光染料标记的纳米颗粒的研究揭示了白血病细胞表面结合和内化。体内生物分布研究显示NP在肝脏和脾脏中蓄积，随后随时间推移颗粒被清除。在白血病的临床前模型中，与游离药物相比，Dex-NPs显著改善了小鼠的生活质量和存活率。据我们所知，这是第一份显示聚合物纳米颗粒递送Dex以潜在治疗儿童白血病的功效的报告，并揭示了低剂量的Dex应足以诱导细胞死亡并提高存活率。
Nanotechnology approaches have tremendous potential for enhancing treatment efficacy with lower doses of chemotherapeutics. Nanoparticle-based drug delivery approaches are poorly developed for childhood leukemia. Dexamethasone (Dex) is one of the most common chemotherapeutic drugs used in the treatment of childhood leukemia. In this study, we encapsulated Dex in polymeric nanoparticles and validated their anti-leukemic potential in vitro and in vivo. Nanoparticles (NPs) with an average diameter of 110 nm were assembled from amphiphilic block copolymers poly (ethylene glycol) (PEG) and poly (ε-caprolactone) (PCL) bearing pendant cyclic ketals. The blank nanoparticles were non-toxic to cultured cells in vitro and to mice in vivo. Encapsulation of Dex into the nanoparticles (Dex-NP) did not compromise the bioactivity of the drug. Dex-NPs induced glucocorticoid phosphorylation and showed cytotoxicity similar to the free Dex in leukemic cells. Studies using nanoparticles labeled with fluorescent dyes revealed leukemic cell surface binding and internalization. In vivo biodistribution studies showed NP accumulation in the liver and spleen with subsequent clearance of the particles with time. In a pre-clinical model of leukemia, Dex-NPs significantly improved the quality of life and survival of mice compared to the free drug. To our knowledge, this is the first report showing the efficacy of polymeric nanoparticles to deliver Dex to potentially treat childhood leukemia and reveals that low dose of Dex should be sufficient for inducing cell death and improve survival.
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