ATB 0,+ -targeted delivery of triptolide prodrugs for safer and more effective pancreatic cancer therapy
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 foun...
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Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2021-02, Vol.33, p.127728 |
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Hauptverfasser: | , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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 ATB
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 ATB
-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 ATB
for pancreatic cancer-selective delivery and treatment. |
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ISSN: | 1464-3405 |