The research on the anti-inflammatory activity and hepatotoxicity of triptolide-loaded solid lipid nanoparticle
The research on the anti-inflammatory activity and hepatotoxicity of triptolide-loaded solid lipid nanoparticle
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DOI：
10.1016/j.phrs.2004.10.007
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发表时间：
2005-04-01
影响因子：
9.3
通讯作者：
Yang, XL
中科院分区：
文献类型：
--
作者：
Mei, ZN;Lia, XK;Yang, XL
雷公藤内酯醇（TP）已被证明具有抗炎，免疫抑制，抗生育和抗肿瘤活性。但由于其严重的毒性，在一定程度上限制了其临床应用。雷公藤甲素肝毒性的机制可能与活性氧（ROS）诱导脂质过氧化和DNA损伤有关。控制释放给药策略的发展将为这些药物的临床应用带来显著的优势，从而降低毒性。因此，本研究的重点是雷公藤甲素固体脂质纳米粒（SLN）的制备和表征，以及TP-SLN的抗炎活性和肝毒性。角叉菜胶致大鼠足跖肿胀实验表明，TP-SLN的抗炎作用强于游离雷公藤内酯醇。在观察期内，每天经口给予0.2或0.4 mg/kg TP-SLN未导致死亡。相反，不同剂量的游离雷公藤内酯醇导致部分死亡。游离雷公藤内酯醇治疗组的血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平显著升高，而TP-SLN治疗组的血清ALT和AST水平无显著变化。游离雷公藤甲素可使肝匀浆中丙二醛（NIDA）含量升高，超氧化物歧化酶（SOD）和总谷胱甘肽过氧化物酶（GSH-Px）活性降低。然而，在TP-SLN治疗的小鼠中未发现这些现象。组织病理学检查结果显示SLN对雷公藤甲素引起的空泡化、水肿、炎性浸润和坏死有保护作用。TP-SLN不改变肝细胞Bcl/Bax蛋白比例，也不降低肝细胞FasL表达。说明SLN给药系统能增强雷公藤甲素的抗炎活性，同时对雷公藤甲素的肝毒性有保护作用。TP-SLN对其他组织的毒性正在研究中。(C)2004爱思唯尔有限公司保留所有权利。
Triptolide (TP) has been shown to have anti-inflammatory, immunosuppressive, anti-fertility and anti-neoplastic activity. However, its clinical use was restricted to some extent due to its serious toxicity. The possible mechanism for triptolide-induced hepatotoxicity was related to reactive oxygen species (ROS) inducing lipid peroxidation and DNA damage. The development of controlled release delivery strategies could lead to significant advantages in the clinical use of these drugs to decreasing the toxicity. Thus, the present study was focused on the preparation and some characterization of triptolide-loaded solid lipid nanoparticle (SLN) and the measurements of anti-inflammatory activities and the hepatotoxicity of TP-SLN. The carrageenan-induced rat paw edema experiment indicated that the anti-inflammatory activities of TP-SLN were stronger than those of free triptolide. Orally administration of TP-SLN 0.2 or 0.4 mg/kg per day did not cause mortality within the period of observation. In contrast, free triptolide at different doses had caused partial death. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly elevated in the free triptolide-treated group whereas they did not significantly change in TP-SLN-treated mice. The free triptolide increased malondialdehyde (NIDA) level and decreased activities of superoxide dismutase (SOD) and total glutathione peroxidase (GSH-Px) in the liver homogenates. However, these phenomena were not found in TP-SLN-treated mice. The results of histopathological evaluation revealed a protective effect of SLN on vacuolation, edema, inflammatory infiltration and necrosis caused by triptolide. Furthermore, TP-SLN did not change Bcl/Bax protein ratio or decrease FasL expression in liver cells. These results suggest that SLN delivery system can enhance the anti-inflammatory activity of triptolide meanwhile has a protective effect against triptolide-induced hepatotoxicity. The toxicity of TP-SLN to other tissues is under investigation. (C) 2004 Elsevier Ltd. All rights reserved.