Loading…

ATB0,+-targeted delivery of triptolide prodrugs for safer and more effective pancreatic cancer therapy

[Display omitted] Triptolide (TP) is a diterpene epoxide component extracted from Tripterygium wilfordii and has been shown to possess an impressive anticancer effect. However, TP has not yet entered any clinic trials due to the severe adverse effects that resulted from the off-target absorption and...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2021-02, Vol.33, p.127728-127728, Article 127728
Main Authors: Lou, Dan, Lou, Zijian, Lin, Yuanzhen, Shangguan, Hao, Lin, Yujie, Luo, Qiuhua, Zhang, Hailin, Lin, Guangyong, Chen, Ruijie, Kou, Longfa, Bao, Shihui
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] Triptolide (TP) is a diterpene epoxide component extracted from Tripterygium wilfordii and has been shown to possess an impressive anticancer effect. However, TP has not yet entered any clinic trials due to the severe adverse effects that resulted from the off-target absorption and distribution found in animal studies. In this study, we designed and synthesized three amino acids (tryptophan, valine, and lysine) based TP prodrugs to target ATB0,+ which are highly expressed in pancreatic cancer cells for more effective pancreatic cancer therapy. The stability, uptake profiles, uptake mechanism, and cancer-killing ability were studied in vitro. All three prodrugs showed increased uptake and enhanced cytotoxicity in pancreatic cancer cells, but not in normal pancreatic cells. The difference in killing effect on normal and cancer cells was attributed to pancreatic cancer over-expressed ATB0,+-mediated uptake. Specifically, tryptophan-conjugated TP prodrug (TP-Trp) showed the highest uptake and the best cancer cell killing effect, considered as the best candidate. The present study provided the proof-of-concept of exploiting TP prodrug to target ATB0,+ for pancreatic cancer-selective delivery and treatment.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2020.127728