School of Pharmaceutical Science and Technology, Dalian University of Technology , No. 2 Linggong Road, Dalian 116024, China.
Chemical Analysis and Research Center, Dalian University of Technology , No. 2 Linggong Road, Dalian 116024, China.
Mol Pharm. 2018 Feb 5;15(2):560-570. doi: 10.1021/acs.molpharmaceut.7b00914. Epub 2018 Jan 22.
Triptolide (TP) has been used as one of the most common systemic treatments for various diseases since the 1960s. However, TP displays diverse side effects on various organs, which limits its clinical application. To overcome this issue, numerous C-14-hydroxyl group derivatives of TP have been synthesized. In this research, the C-14-hydroxyl group of TP is modified by a cell-penetrating peptide polyarginine (R). The derivative TP-disulfide-CR (TP-S-S-CR) containing a disulfide linkage between TP and R possesses less toxicity at various concentrations on the immortal human keratinocyte (HaCaT) cell line by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay compared with free TP. Treating HaCaT cells with TP (100 nM) could increase intracellular ROS (reactive oxygen species) and decrease the activity of SOD (superoxide dismutase). Meanwhile, treating HaCaT cells with equimolar concentration of TP-S-S-CR did not cause both of the above TP-induced alterations. In addition, TP-S-S-CR did not show significant dermal toxicity on guinea pigs and could efficiently overcome the barrier of corneum and then reach epidermis and dermis within 2 h of transdermal administration. In addition, there was a relatively lower concentration of TP in blood indicating less toxicity on organs. Such results suggest that topical therapy using polyarginine is possible by the transdermal delivery of TP.
雷公藤红素（TP）自 20 世纪 60 年代以来一直被用作治疗各种疾病的最常用的全身治疗方法之一。然而，TP 在各种器官上表现出不同的副作用，限制了其临床应用。为了克服这个问题，已经合成了许多 TP 的 C-14-羟基衍生物。在这项研究中，通过细胞穿透肽聚精氨酸（R）修饰 TP 的 C-14-羟基。含有 TP 和 R 之间二硫键的衍生物 TP-二硫键-CR（TP-S-S-CR）在各种浓度下对永生化人角质形成细胞（HaCaT）细胞系的毒性低于游离 TP，通过 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴化物（MTT）测定法。用 TP（100 nM）处理 HaCaT 细胞可增加细胞内 ROS（活性氧）并降低 SOD（超氧化物歧化酶）的活性。同时，用等摩尔浓度的 TP-S-S-CR 处理 HaCaT 细胞不会引起上述两种由 TP 诱导的改变。此外，TP-S-S-CR 对豚鼠没有明显的皮肤毒性，并且能够在透皮给药 2 小时内有效地克服角质层的屏障，然后到达表皮和真皮。此外，血液中 TP 的浓度相对较低，表明对器官的毒性较小。这些结果表明，通过透皮给药，使用聚精氨酸的局部治疗是可能的。
