Liu Hongyan, Gao Meng, Xu Hong, Guan Xin, Lv Li, Deng Sa, Zhang Chenghong, Tian Yan
College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
Pharm Res. 2016 Jan;33(1):217-36. doi: 10.1007/s11095-015-1781-4. Epub 2015 Sep 3.
Emodin (EMO) has multi-targets and multi-way antitumor effect, which was limited by the instability and poor solubility of EMO. The aim of this study was to formulate EMO-loaded poly (lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate (PLGA-TPGS) nanoparticles (EPTN) to increase the liver targeting of EMO for cancer therapy.
EMO/coumarin-6-loaded PLGA-TPGS nanoparticles (ECPTN) and EMO-loaded PLGA nanoparticles (EPN) were also prepared as comparison. The cellular uptake of ECPTN by HepG2 and HCa-F cells was investigated using Confocal laser scanning microscopy. The apoptosis of HepG2 cells handled with EPTN was assayed by flow cytometry. The liver targeting property of ECPTN in mice was evaluated using the drug concentration determined by RP-HPLC and the freezing slices were investigated via fluorescence inversion microscopy. The blood samples were obtained from vein intubation to illustrate the pharmacokinetics process of EPTN. The tumor-bearing mice model was established to elucidate the in vivo therapeutic effect of EPTN.
The results demonstrated that ECPTN could be internalized by HepG2 and HCa-F cells respectively. The ratio of apoptosis cells was increased after dealing with EPTN. The detection indexes of drug concentration and fluorescence inversion microscopy images indicated ECPTN had an excellent effect on liver targeting property than EMO solutions (EMS). The pharmacokinetics process of EPTN showed obvious sustained-release effect than EMS. Compared with EPN, the in vivo antitumor activity of EPTN against tumor cells were better.
In conclusion, EPTN could be used in the treatment of liver cancer acted as a kind of promising intravenous dosage forms.
大黄素（EMO）具有多靶点、多途径的抗肿瘤作用，但其不稳定性和低溶解度限制了其应用。本研究旨在制备负载EMO的聚（丙交酯-乙交酯）-d-α-生育酚聚乙二醇1000琥珀酸酯（PLGA-TPGS）纳米粒（EPTN），以提高EMO对肝癌治疗的肝靶向性。
作为对照，还制备了负载EMO/香豆素-6的PLGA-TPGS纳米粒（ECPTN）和负载EMO的PLGA纳米粒（EPN）。采用共聚焦激光扫描显微镜研究了ECPTN被HepG2和HCa-F细胞的摄取情况。通过流式细胞术检测EPTN处理后HepG2细胞的凋亡情况。采用反相高效液相色谱法测定药物浓度，通过荧光倒置显微镜观察冷冻切片，评估ECPTN在小鼠体内的肝靶向特性。通过静脉插管采集血样，以阐明EPTN的药代动力学过程。建立荷瘤小鼠模型，以阐明EPTN的体内治疗效果。
结果表明，ECPTN可分别被HepG2和HCa-F细胞内化。用EPTN处理后，凋亡细胞比例增加。药物浓度检测指标和荧光倒置显微镜图像表明，ECPTN的肝靶向特性优于EMO溶液（EMS）。EPTN的药代动力学过程显示出比EMS更明显的缓释效果。与EPN相比，EPTN对肿瘤细胞的体内抗肿瘤活性更好。
总之，EPTN作为一种有前景的静脉给药剂型，可用于肝癌治疗。
