An optimized two-vial formulation lipid nanoemulsion of paclitaxel for targeted delivery to tumor
An optimized two-vial formulation lipid nanoemulsion of paclitaxel for targeted delivery to tumor
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DOI：
10.1016/j.ijpharm.2017.10.005
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发表时间：
2017-12-20
影响因子：
5.8
通讯作者：
Chen, Jianming
中科院分区：
文献类型：
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作者：
Chen, Lina;Chen, Bingchen;Chen, Jianming
开发水不溶性药物的新型静脉给药载体是一个具有挑战性的课题。本文研究了紫杉醇（PTX）脂质纳米乳剂（TPLE-1）、220 nm（TPLE-2）和380 nm（TPLE-3）的新型两瓶制剂，这些制剂是通过在使用前混合PTX的PEG 400溶液和10%（w/w）不同粒径的空白脂质乳剂（BLE）形成的，并对它们的药剂学、药代动力学、生物分布、体内外抗癌效果进行了比较评价。其中，TPLE-1具有较高的载药量、较慢的释放速度和较大的油相分布，显著减少RES器官的提取，增加肿瘤摄取，对MCF-7细胞显示出较强的细胞毒性，对MCF-7荷瘤裸鼠显示出较强的抗癌效果，并且具有较大的血浆AUC（0-无穷大）值、较小的血浆清除率（CL）、较长的平均滞留时间（MRT）和消除半衰期（T-1/2）。它还表现出与Taxol（R）相同的体内功效，甚至产生更少的溶血和静脉内刺激。此外，它的LD 50比Taxol（R）高4.3倍。结果表明，TPLE-1具有高肿瘤蓄积性、低毒性、安全性和可药用性，是一种很有前途的肿瘤治疗候选药物。
The discovery of new intravenous drug delivery carrier for water-insoluble drug is a challenging task. In this paper, novel two-vial formulation of paclitaxel (PTX)-loaded lipid nanoemulsions (TPLEs) with particle sizes of 110 nm (TPLE-1), 220 nm (TPLE-2) and 380 nm (TPLE-3), which were formed by mixing a PEG400 solution of PTX and 10% (w/w) blank lipid emulsions (BLEs) with different particle size prior to use, were developed and comparatively evaluated for their pharmaceutics, pharmacokinetics, biodistribution, in vitro and in vivo anticancer efficiency. Among them, TPLE-1 displayed higher PTX-loading, slower PTX-release and larger PTX-distribution in oil-phase, significantly reduced extraction by RES organs, increased tumor-uptake, showed stronger cytotoxicity against MCF-7 cells and more potent anticancer efficacy on MCF-7 tumor-bearing nude mice, and had greater plasma AUC(0-infinity) value, smaller plasma clearance (CL), longer mean residence time (MRT) and elimination half-life (T-1/2) in SD rats. It also exhibited the same in vivo efficacy as Taxol (R) and even produced less hemolysis and intravenous irritation. Moreover, its LD50 was 4.3-fold higher than that of Taxol (R). All results demonstrate that TPLE-1 is a promising candidate drug due to its high tumor-accumulation and effectiveness, low toxicity, good safety and druggability in clinical application for the cancer therapy.