Docetaxel-loaded PEO-PPO-PCL/TPGS mixed micelles for overcoming multidrug resistance and enhancing antitumor efficacy
Docetaxel-loaded PEO-PPO-PCL/TPGS mixed micelles for overcoming multidrug resistance and enhancing antitumor efficacy
复制标题
负载多西他赛的 PEO-PPO-PCL/TPGS 混合胶束克服多药耐药性并增强抗肿瘤功效
DOI：
10.1039/c5tb00401b
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Luan Yuxia
中科院分区：
文献类型：
--
作者：
Shi Chunhuan;Zhang Zhiqing;Wang Fang;Ji Xiaoqing;Zhao Zhongxi;Luan Yuxia
目前的抗癌药物递送系统存在两个主要障碍。一个是多药耐药（MDR）的出现，另一个是长循环和细胞摄取之间的冲突。采用PEO-PPO-PCL与D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）的混合物，通过自组装将抗癌药物多西他赛（DTX）成功地负载到3个系列的胶束中，以达到延长血液循环时间和克服DTX多药耐药的目的。合成了三种不同分子量的聚己内酯共聚物PEO 68-PPO 34-PCL 9、PEO 68-PPO 34-PCL 18和PEO 68-PPO 34-PCL 36。所制备的球形混合胶束（MM）具有纳米尺寸（25-135 nm）。PEO-PPO-PCL/TPGS混合胶束具有低临界胶束浓度（≤ 10 - 6 g mL-1）和低溶血率（<5%），这证明它们在体内使用是安全的。同时，它们在体外具有明显的缓释作用，在体内循环时间比游离DTX长。P-gp抑制实验、细胞摄取实验和MTT实验结果表明，载药MM能克服肿瘤细胞的MDR，细胞摄取率和抗肿瘤效果均高于游离MTX。IC 50值表明，在用MCF-7细胞处理72小时后，三个系列的载DTX MM分别是游离DTX的69、82和100倍。因此，这些结果表明，所制备的载有DTX的MM在癌症化疗中提供了理想的应用。
There are two major hurdles for the current anti-cancer drug delivery systems. One is the emergence of multidrug resistance (MDR) and the other is the conflict between long-circulation and cellular uptake. In the present study, the anticancer drug docetaxel (DTX) was successfully loaded into three series of micelles via self-assembly using a mixture of PEO–PPO–PCL and D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS), for the purpose of prolonging the blood circulation time as well as overcoming MDR of DTX. Three series of copolymers with different PCL molecular weights, PEO68–PPO34–PCL9, PEO68–PPO34–PCL18 and PEO68–PPO34–PCL36, were synthesized. The prepared spherical mixed micelles (MM) were found to possess nanoscale size (25–135 nm). The PEO–PPO–PCL/TPGS mixed micelles had a low critical micelle concentration (∼10−6 g mL−1) and a low hemolysis rate (<5%), which has proved that they are safe for use in vivo. Moreover, they had obvious sustained release behavior in vitro and a longer circulation time than free DTX in vivo. The P-gp inhibition assay, cellular uptake and MTT assay in cancer cells exhibited that DTX-loaded MM could overcome MDR, show higher cellular uptake and higher antitumor efficacy than free DTX. The IC50 values demonstrated that the three series of DTX-loaded MM were 69, 82 and 100 fold effective than free DTX after 72 h treatment with MCF-7 cells, respectively. Therefore, these results demonstrated that the prepared DTX-loaded MM provide desirable application in cancer chemotherapy.