pH-responsive artemisinin dimer in lipid nanoparticles are effective against human breast cancer in a xenograft model.
pH-responsive artemisinin dimer in lipid nanoparticles are effective against human breast cancer in a xenograft model.
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DOI：
10.1002/jps.24407
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发表时间：
2015-05
影响因子：
3.8
通讯作者：
Sasaki T
中科院分区：
文献类型：
--
作者：
Zhang YJ;Zhan X;Wang L;Ho RJ;Sasaki T
青蒿素（ART）是一种众所周知的抗疟药，也具有抗癌活性。我们先前报道了一组具有pH依赖性水溶性的新型二聚青蒿素哌嗪缀合物（ADP）和基于天然卵磷脂（EPC）的概念验证脂质纳米粒制剂。EPC可诱导对蛋制品敏感的个体发生过敏反应。因此，本报告的目的是开发适合体内评价的ADP合成脂质颗粒。我们发现ADP以大于90%的效率与1，2-二棕榈酰-sn-甘油-3-磷酸胆碱（DPPC）结合并形成药物-脂质颗粒（d ~ 80 nm）。ADP药物脂质颗粒的冷冻电子显微镜显示单层囊泡样结构。详细的表征研究显示ADP先导化合物ADP 109插入DPPC膜中并存在水性核。在pH 4下，超过50%的ADP 109在48小时内释放，而在中性下不到20%。ADP 109-脂质颗粒对人乳腺癌表现出高效力，但非致瘤细胞耐受良好。在MDA-MB-231小鼠异种移植模型中，脂质结合的ADP 109颗粒在控制肿瘤生长方面比紫杉醇更有效。细胞摄取研究显示纳米颗粒的内吞作用和在37°C下在整个胞质溶胶中释放核心捕获的标记物。这些结果首次证明了脂质结合的ART二聚体用于癌症化疗的体内可行性。
Artemisinin (ART), a well-known antimalaria drug, also exhibits anticancer activities. We previously reported a group of novel dimeric artemisinin piperazine conjugates (ADPs) possessing pH-dependent aqueous solubility and a proof-of-concept lipid nanoparticle formulation based on natural egg phosphatidylcholine (EPC). EPC may induce allergic reactions in individuals sensitive to egg products. Therefore, the goal of this report is to develop ADP-synthetic lipid particles suitable for in vivo evaluation. We found that ADP binds to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) with greater than 90% efficiency and forms drug–lipid particles (d ~ 80 nm). Cryo-electron microscopy of the ADP drug–lipid particles revealed unilamellar vesicle-like structures. Detailed characterization studies show insertion of the ADP lead compound, ADP109, into the DPPC membrane and the presence of an aqueous core. Over 50% of the ADP109 was released in 48 hours at pH4 compared with less than 20% at neutral. ADP109–lipid particles exhibited high potency against human breast cancer, but was tolerated well by nontumorigenic cells. In MDA-MB-231 mouse xenograft model, lipid-bound ADP109 particles were more effective than paclitaxel in controlling tumor growth. Cellular uptake studies showed endocytosis of the nanoparticles and release of core-trapped marker throughout the cytosol at 37°C. These results demonstrate, for the first time, the in vivo feasibility of lipid-bound ART dimer for cancer chemotherapy.