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论文类型：期刊论文

发表时间：2018-02-01

发表刊物：MOLECULAR PHARMACEUTICS

收录刊物：SCIE、PubMed、Scopus

卷号：15

期号：2

页面范围：560-570

ISSN号：1543-8384

关键字：triptolide; cell-penetrating peptide; toxicity reduction; drug modification

摘要：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-7). The derivative TP-disulfide-CR7 (TP-S-S-CR7) containing a disulfide linkage between TP and R-7 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-CR7 did not cause both of the above TP-induced alterations. In addition, TP-S-S-CR7 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.