Li Xue, Mao Yuling, Li Kai, Shi Tianyu, Yao Huimin, Yao Jianhua, Wang Shujun
a School of Chinese Medicines, Shenyang Pharmaceutical University , Shenyang , China .
b Department of Pharmaceutics , School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China .
Drug Deliv. 2016 May;23(4):1344-54. doi: 10.3109/10717544.2015.1028603. Epub 2015 Apr 8.
Triptolide (TP) shows strong anti-tumor activities on various cancer cells, especially on pancreatic cancer. TP inhibits HSP70 expression leading to cell death in pancreatic cancer cells and induces cell death by apoptotic and autophagic pathways. In order to increase the therapeutic index of TP, a novel intravenous TP-loaded delivery system, TP-loaded lipid emulsion (TP-LE), has been developed to treat solid tumor. In the present study, the preparation and characterization of TP-LE were described. The pharmacokinetics and tissue distribution study of TP-LE in mice were also evaluated. Results demonstrated that TP-LE had an average particle size of 154.6 nm, entrapment efficiency (EE%) of 87%, zeta potential of -0.903 mV and autoclaved stability. The pharmacokinetic study showed that blood concentrations of both TP-LE and TP reached a maximum at the end of intravenous administration (1.25 mg/kg) and declined rapidly within the first 10 min with a mean residence time (MRT) of about 10 min. In the tissue distribution study, a preferential accumulation and longer residence time of drug in pancreas were found in TP-LE. The AUC0-60min of TP-LE in pancreas was 2.19 times in comparison to free TP, suggesting that the use of TP-LE conferred improvements in biodistribution, accumulation and therapeutic efficacy in pancreas. Moreover, the concentrations of TP-LE in heart, lung and kidney were lower than that of the TP group, indicating the potential for reduced toxicity of TP-LE. Together, all the results show that TP-LE appears to be a promising formulation for using TP in treating cancer, and more specifically pancreatic cancer.
雷公藤甲素（TP）对多种癌细胞具有强大的抗肿瘤活性，尤其是对胰腺癌。TP抑制热休克蛋白70（HSP70）的表达，导致胰腺癌细胞死亡，并通过凋亡和自噬途径诱导细胞死亡。为了提高TP的治疗指数，已开发出一种新型的静脉注射载TP给药系统——载TP脂质乳剂（TP-LE），用于治疗实体瘤。在本研究中，描述了TP-LE的制备和表征。还评估了TP-LE在小鼠体内的药代动力学和组织分布研究。结果表明，TP-LE的平均粒径为154.6 nm，包封率（EE%）为87%，ζ电位为-0.903 mV，且具有高压灭菌稳定性。药代动力学研究表明，TP-LE和TP的血药浓度在静脉注射（1.25 mg/kg）结束时达到最大值，并在最初10分钟内迅速下降，平均驻留时间（MRT）约为10分钟。在组织分布研究中，发现TP-LE在胰腺中具有优先蓄积和更长的驻留时间。TP-LE在胰腺中的AUC0-60min是游离TP的2.19倍，表明使用TP-LE可改善胰腺中的生物分布、蓄积和治疗效果。此外，TP-LE在心脏、肺和肾脏中的浓度低于TP组，表明TP-LE具有降低毒性的潜力。总之，所有结果表明，TP-LE似乎是一种有前景的制剂，可用于使用TP治疗癌症，尤其是胰腺癌。
