Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation

• Published in: Angewandte Chemie International Edition 2016-09, Vol.55 (39), p.12035-12039
• Main Authors: He, Qing-Li, Minn, Il, Wang, Qiaoling, Xu, Peng, Head, Sarah A., Datan, Emmanuel, Yu, Biao, Pomper, Martin G., Liu, Jun O.
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Antitumor activity; Antitumor agents; Autoimmune diseases; Biocompatibility; Cell Line, Tumor; Cell Survival - drug effects; Conjugation; Cytotoxicity; Diterpenes - administration & dosage; Diterpenes - chemistry; Diterpenes - therapeutic use; DNA-directed RNA polymerase; Drug Delivery Systems; Epoxy Compounds - administration & dosage; Epoxy Compounds - chemistry; Epoxy Compounds - therapeutic use; Glucose; Glucose - chemistry; glucose transporters; HEK293 Cells; Herbal medicine; Humans; Medicinal plants; Mice; Neoplasms - drug therapy; Phenanthrenes - administration & dosage; Phenanthrenes - chemistry; Phenanthrenes - therapeutic use; Prostate cancer; RNA polymerase; RNA polymerase II; Solubility; Toxicity; Triptolide; Tumor cells; Water pollution
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201606121

Triptolide, a key ingredient from the traditional Chinese medicinal plant thunder god vine, which has been used to treat inflammation and autoimmune diseases for centuries, has been shown to be an irreversible inhibitor of the XPB subunit of the transcription factor TFIIH and initiation of RNA polymerase II mediated transcription. The clinical development of triptolide over the past two decades has been limited by its toxicity and low water solubility. Herein, we report the development of a glucose conjugate of triptolide, named glutriptolide, which was intended to target tumor cells overexpressing glucose transporters selectively. Glutriptolide did not inhibit XPB activity in vitro but demonstrated significantly higher cytotoxicity against tumor cells over normal cells with greater water solubility than triptolide. Furthermore, it exhibited remarkable tumor control in vivo, which is likely due to sustained stepwise release of active triptolide within cancer cells. These findings indicate that glutriptolide may serve as a promising lead for developing a new mechanistic class of anticancer drugs. A glucose conjugate of the anti‐inflammatory natural product triptolide, glutriptolide, was developed that selectively targets tumor cells overexpressing glucose transporters. Glutriptolide demonstrated significantly higher cytotoxicity against tumor cells than against normal cells and also benefitted from improved water solubility compared with triptolide.