Liver-targeting Resibufogenin-loaded poly(lactic-co-glycolic acid)-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles for liver cancer therapy.
Liver-targeting Resibufogenin-loaded poly(lactic-co-glycolic acid)-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles for liver cancer therapy.
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用于肝癌治疗的肝脏靶向负载 Resibufogenin 的聚（乳酸-乙醇酸）-D-α-生育酚聚乙二醇 1000 琥珀酸酯纳米颗粒
DOI：
10.2147/ijn.s93541
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发表时间：
2016
影响因子：
8
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Chu Q;Xu H;Gao M;Guan X;Liu H;Deng S;Huo X;Liu K;Tian Y;Ma X
肝癌仍然是世界各地的一个主要问题。脂蟾毒配基（Resibufogenin，RBG）是从蟾毒（也称为蟾毒或蟾毒）中分离得到的一种主要生物活性化合物，蟾毒是从巨型蟾蜍的皮肤分泌物中获得的一种流行的传统中药。RBG具有很强的抗肿瘤作用，但其水溶性差和心脏毒性限制了其临床应用。本研究的目的是制备载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）以增强肝癌的治疗。制备了RPTN、RBG负载的PLGA纳米粒（RPN）和RBG/香豆素-6负载的PLGA-d-α-生育酚聚乙二醇1000琥珀酸酯纳米粒（RCPTN）。用激光共聚焦显微镜观察HepG 2和HCa-F细胞对RCPTN的摄取情况。用流式细胞术检测RPTN、RBG溶液（RS）和5-氟尿嘧啶溶液（用作阴性对照）诱导HepG 2细胞凋亡。测定RS和RPTN的LD 50（半数致死量）值，并测定RCPTN在静脉注射小鼠中的肝靶向特性。在大鼠中进行了药代动力学研究，并在小鼠肿瘤模型中检查了RPTN、RPN和RS的体内治疗效果。结果表明，RCPTN同时将香豆素-6和RBG递送到HepG 2和HCa-F细胞中。RPTN组凋亡细胞比例增加。RPTN的LD 50是RS值的2.02倍。与RS相比，RPTN和RPN在体内无论是药效学研究还是抗肿瘤疗效方面均显示出显著差异，且RPTN的表现明显优于RPN。药物浓度检测指标和荧光倒置显微镜图像检测指标均表明RCPTN的肝靶向性明显优于RS。肝靶向RPTN，其显示出增强的药理作用和降低的毒性的负载药物RBG，因此是一种有前途的静脉注射剂型，可能是有用的，在治疗肝癌。
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.