目的：探讨载阿帕替尼（apatinib）纳米胶束对脐静脉内皮细胞（HUVECs）的抑制作用及其释放规律与安全性。方法：分别用紫外-吸收法和溶血实验检测载apatinib纳米胶束的释放率与使用安全性，然后分别用CCK-8实验、迁移实验、体外小管形成实验观察载apatinib纳米胶束对HUVECs的抑制作用。结果：载apatinib纳米胶束有短暂的突释效应（2 h达20.5%），随后呈缓慢释放（72 h达62.9%），其溶血实验阴性。载apatinib纳米胶束与单纯apatinib均能明显抑制HUVECs的增殖，并呈浓度与时间依赖性（均P<0.05）；48 h内载apatinib纳米胶束对HUVECs的抑制率小于单纯apatinib组（48 h IC50：1.385 µmol/L vs. 0.768 µmol/L，P=0.012），但随着时间延长至72 h，载apatinib纳米胶束的抑制率超过单纯apatinib（63.34% vs. 59.70%，P=0.005）。载apatinib纳米胶束与单纯apatinib均能明显抑制HUVECs的迁移及小管形成，并呈浓度与释放时间依赖性，且体外释放3 d的载apatinib纳米胶束对HUVECs迁移及成管的抑制超过单纯apatinib（均P<0.05）。结论：载apatinib纳米胶束具备良好的安全性及缓释性，对apatinib进行纳米包载可增强apatinib对HUVECs的抑制作用并延长apatinib的作用时间窗。
Inhibitory effect of apatinib-loaded nanomicelles on human umbilical vein endothelial cells
Objective: To investigate the inhibitory effect of apatinib-loaded nanomicelles on human umbilical vein endothelial cells (HUVECs) as well as its release pattern and safety. Methods: The release rate and use safety of apatinib-loaded nanomicelles was determined by ultraviolet spectrophotometry method and hemolytic assay, respectively. And then, the inhibitory effect of apatinib-loaded nanomicelles on HUVECs was tested by CCK-8 assay, migration assay and tube formation assay, respectively. Results: The apatinib-loaded nanomicelles showed a transient immediate-release (2 h release rate reached 20.5%) and then a slow release (72 h release rate was 62.9%), and the results of hemolytic assay were negative. The proliferation of HUVECs was significantly inhibited by either apatinib-loaded nanomicelles or free apatinib in a concentration- and time-dependent manner (all P<0.05); the inhibition rate of apatinib-loaded nanomicelles on HUVECs was lower than those of free apatinib within 48 h (48 h IC50: 1.385 µmol/L vs. 0.768 µmol/L, P=0.012), but it surpassed that of free apatinib with time up to 72 h (63.34% vs. 59.70%, P=0.005). The migration and tube formation of HUVECs were significantly suppressed by both apatinib-loaded nanomicelles and free apatinib in a concentration- and releasing time-dependent manner, and the inhibitory effects of apatinib-loaded nanomicelles with 3-d release on migration and tube formation of HUVECs were significantly greater than those of free apatinib (both P<0.05). Conclusion: The apatinib-loaded nanomicelles have good safety and sustained release property. Nanoencapsulation can enhance the inhibitory effect of apatinib on HUVECs and extend its action time window.