Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Wenzhou 325027, China.
Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China.
Bioorg Med Chem Lett. 2021 Feb 1;33:127728. doi: 10.1016/j.bmcl.2020.127728. Epub 2020 Dec 17.
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.
雷公藤红素（TP）是从雷公藤中提取的二萜环氧成分，具有显著的抗癌作用。然而，由于在动物研究中发现的脱靶吸收和分布导致严重的不良反应，TP 尚未进入任何临床试验。在这项研究中，我们设计并合成了三种基于氨基酸（色氨酸、缬氨酸和赖氨酸）的 TP 前药，以靶向在胰腺癌细胞中高度表达的 ATB，从而更有效地治疗胰腺癌。我们在体外研究了它们的稳定性、摄取谱、摄取机制和杀伤癌细胞的能力。三种前药在胰腺癌细胞中的摄取和细胞毒性均增强，但在正常胰腺细胞中没有。正常细胞和癌细胞杀伤效果的差异归因于胰腺癌细胞过度表达的 ATB 介导的摄取。具体来说，色氨酸偶联的 TP 前药（TP-Trp）表现出最高的摄取和最好的癌细胞杀伤效果，被认为是最佳候选药物。本研究为利用 TP 前药靶向 ATB 进行胰腺癌选择性递药和治疗提供了概念验证。
