Co-delivery of PDTC and doxorubicin by multifunctional micellar nanoparticles to achieve active targeted drug delivery and overcome multidrug resistance
Co-delivery of PDTC and doxorubicin by multifunctional micellar nanoparticles to achieve active targeted drug delivery and overcome multidrug resistance
复制标题
通过多功能胶束纳米粒子共同递送PDTC和阿霉素，实现主动靶向药物递送并克服多药耐药性。
DOI：
10.1016/j.biomaterials.2010.03.066
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发表时间：
2010-07-01
期刊：
影响因子：
14
通讯作者：
Zhang, Shengyong
中科院分区：
文献类型：
--
作者：
Fan, Li;Li, Fei;Zhang, Shengyong
由叶酸壳聚糖共聚物（FA - CS）自组装形成的胶束纳米粒子被用作载体，共同递送吡咯烷二硫代氨基甲酸酯（PDTC）和阿霉素（DOX），以实现阿霉素的靶向递送、pH响应性药物释放，并克服阿霉素的多药耐药性（MDR）。通过核磁共振确定了FA - CS的成功合成。平均粒径足够小，能够在体循环中保持较长时间。在中性和弱碱性条件下较低的临界聚集浓度（CACs），而非酸性pH值，可能使胶束纳米粒子在血流中保持良好的稳定性。胶束纳米粒子对阿霉素和PDTC的包封率分别为77.64%和86.54%（重量百分比），载药量分别为12.34%和15.32%（重量百分比）。在中性或弱碱性pH值下，阿霉素的释放缓慢且持续，然而在弱酸性环境中，释放速度要快得多，在最初的2小时内接近其总药物含量的75 - 95%被释放出来。载阿霉素胶束纳米粒子的半数抑制浓度（IC50）较低，表明FA - CS胶束极大地提高了细胞摄取效率。荧光显微镜照片进一步证实，从CS - FA胶束中释放的阿霉素对pH敏感，并实现了细胞内靶向。通过流式细胞术分析证实，除了叶酸受体介导的内吞作用过程外，PDTC和阿霉素的共同递送可能进一步克服阿霉素的多药耐药性。这种共同递送系统可能对肝癌具有重要的临床意义。（c）2010爱思唯尔有限公司。保留所有权利。
Micellar nanoparticles self-assembled from copolymer folate chitosan (FA CS) were employed as carriers to co-deliver Pyrrolidinedithiocarbamate (PDTC) and doxorubicin (DOX) to achieve targeted DOX delivery, with a pH responsive drug release, and to overcome DOX multidrug resistance (MDR). The successful synthesis of FA-CS was determined by NMR. Average particle size was small enough to achieve longevity during systemic circulation. Lower CACs in neutral and alkalescent conditions rather than an acid pH may lead to maintenance of good stability of the micellar nanoparticles in the blood stream. DOX and PDTC encapsulating efficiencies of the micellar nanoparticles were 77.64 and 86.54 wt% while loading content was 12.34 and 15.32 wt%, respectively. The release of DOX at neutral or alkalescent pH was slow and sustained, however, in the weak acidic environment, was much faster with close to 75-95% of its total drug content being released within the first 2 h. A lower IC50 of DOX-loaded micellar nanoparticles suggested that FA-CS micelles greatly enhanced the cellular uptake efficiency. Fluorescence microscopy micrographs further verified that DOX released from CS-FA micelles could be pH sensitive and achieved intracellular targeting. It was confirmed by flow cytometry analysis that co-delivery of PDTC and DOX may further overcome the MDR of DOX besides the folate receptor mediated endocytosis process. This co-delivery system may have important clinical implications against liver cancers. (c) 2010 Elsevier Ltd. All rights reserved.