Chu Qiuchen, Xu Hong, Gao Meng, Guan Xin, Liu Hongyan, Deng Sa, Huo Xiaokui, Liu Kexin, Tian Yan, Ma Xiaochi
College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
College of Basic Medical Sciences, Dalian Medical University, Dalian, People's Republic of China.
Int J Nanomedicine. 2016 Jan 27;11:449-63. doi: 10.2147/IJN.S93541. eCollection 2016.
Liver cancer remains a major problem around the world. Resibufogenin (RBG) is a major bioactive compound that was isolated from Chansu (also called toad venom or toad poison), which is a popular traditional Chinese medicine that is obtained from the skin secretions of giant toads. RBG has strong antitumor effects, but its poor aqueous solubility and its cardiotoxicity have limited its clinical use. The aim of this study was to formulate RBG-loaded poly(lactic-co-glycolic acid) (PLGA)-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RPTN) to enhance the treatment of liver cancer. RPTN, RBG-loaded PLGA nanoparticle (RPN), and RBG/coumarin-6-loaded PLGA-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RCPTN) were prepared. The cellular uptake of RCPTN by HepG2 and HCa-F cells was analyzed using confocal laser scanning microscopy. Apoptosis was induced in HepG2 cells by RPTN, RBG solution (RS), and 5-fluorouracil solution (used as the negative controls), as assayed using flow cytometry. LD50 (median lethal dose) values were determined for RS and RPTN, and the liver-targeting properties were determined for RCPTN in intravenously injected mice. A pharmacokinetic study was conducted in rats, and the in vivo therapeutic effects of RPTN, RPN, and RS were examined in a mouse tumor model. The results showed that RCPTN simultaneously delivered both coumarin-6 and RBG into HepG2 and HCa-F cells. The ratio of apoptotic cells was increased in the RPTN group. The LD50 for RPTN was 2.02-fold higher than the value for RS. Compared to RS, RPTN and RPN both showed a significant difference in vivo not only in the pharmacodynamic study but also in anticancer efficacy, and RPTN performed much better than RPN. The detection indexes for drug concentration and fluorescence inversion microscopy images both demonstrated that RCPTN was much better at targeting the liver than RS. The liver-targeting RPTN, which displayed enhanced pharmacological effects and decreased toxicity for the loaded drug RBG, is therefore a promising intravenous dosage form that may be useful in the treatment of liver cancer.
肝癌仍然是全球范围内的一个主要问题。脂蟾毒配基（RBG）是一种主要的生物活性化合物，它是从蟾酥（也称为蟾蜍毒液或蟾酥）中分离出来的，蟾酥是一种常见的传统中药，取自大蟾蜍的皮肤分泌物。RBG具有很强的抗肿瘤作用，但其较差的水溶性和心脏毒性限制了其临床应用。本研究的目的是制备负载RBG的聚乳酸-羟基乙酸共聚物（PLGA）-D-α-生育酚聚乙二醇1000琥珀酸酯纳米粒（RPTN），以增强肝癌治疗效果。制备了RPTN、负载RBG的PLGA纳米粒（RPN）和负载RBG/香豆素-6的PLGA-D-α-生育酚聚乙二醇1000琥珀酸酯纳米粒（RCPTN）。使用共聚焦激光扫描显微镜分析了HepG2和HCa-F细胞对RCPTN的细胞摄取情况。通过流式细胞术检测，RPTN、RBG溶液（RS）和5-氟尿嘧啶溶液（用作阴性对照）诱导HepG2细胞凋亡。测定了RS和RPTN的半数致死剂量（LD50）值，并在静脉注射小鼠中测定了RCPTN的肝靶向特性。在大鼠中进行了药代动力学研究，并在小鼠肿瘤模型中考察了RPTN、RPN和RS的体内治疗效果。结果表明，RCPTN能将香豆素-6和RBG同时递送至HepG2和HCa-F细胞中。RPTN组凋亡细胞比例增加。RPTN的LD50比RS的值高2.02倍。与RS相比，RPTN和RPN在体内不仅在药效学研究中，而且在抗癌疗效方面均表现出显著差异，且RPTN的表现远优于RPN。药物浓度检测指标和荧光倒置显微镜图像均表明，RCPTN的肝靶向性远优于RS。因此，具有增强药理作用且对负载药物RBG毒性降低的肝靶向性RPTN是一种有前景的静脉剂型，可能对肝癌治疗有用。
