Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs
Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs
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DOI：
10.1158/1535-7163.mct-04-0290
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发表时间：
2005-04-01
影响因子：
5.7
通讯作者：
Amidon, GL
中科院分区：
文献类型：
--
作者：
Landowski, CP;Vig, BS;Amidon, GL
氟尿苷是一种临床证明的抗癌药物，用于治疗转移性结肠癌和肝转移癌。然而，前药策略可能是必要的，以改善其物理化学性质和选择性，并减少不良的毒性影响。先前针对PEPT1转运体的核苷类药物的氨基酸酯前药的研究，以及最近发现的PEPT1寡肽转运体在胰腺癌细胞系中的功能表达，都表明PEPT1有可能成为癌症治疗的靶点。在这份报告中，我们展示了在高表达PEPT1的细胞系统中实现氟尿嘧啶氨基酸酯类前药增强转运和选择性抗增殖作用的可行性。所有前药均与PEPT-1有亲和力(IC_(50)为1.1~2.3 mmol/L)。然而，与HeLa细胞相比，只有Pro和赖氨酰前药对HeLa/PEPT1细胞的摄取增强(2~8倍)，这表明天冬氨酸基前药是PEPT1抑制剂。前药对MDCK/PEPT1细胞的选择性生长抑制作用与其转运的程度一致。所有酯类前药在Caco-2细胞和MDCK匀浆中降解为氟尿苷的速度最快，在人血浆中最慢，在pH 6.0缓冲液中最稳定。在缓冲液和细胞匀浆中，与天冬氨酸氨基前药相比，Pro和赖氨酰前药的稳定性相对较差。结果表明，通过将稳定性和运输特性结合起来，靶向递送的最佳设计将是可能的。促销。
Floxuridine is a clinically proven anticancer agent in the treatment of metastatic colon carcinomas and hepatic metastases. However, prodrug strategies may be necessary to improve its physiochemical properties and selectivity and to reduce undesirable toxicity effects. Previous studies with amino acid ester prodrugs of nucleoside drugs targeted to the PEPT1 transporter coupled with recent findings of the functional expression of the PEPT1 oligopeptide transporter in pancreatic adenocarcinoma cell lines suggest the potential of PEPT1 as therapeutic targets for cancer treatment. In this report, we show the feasibility of achieving enhanced transport and selective antiproliferative action of amino acid ester prodrugs of floxuridine in cell systems overexpressing PEPT1. All prodrugs exhibited affinity for PEPT 1 (IC50, 1.1-2.3 mmol/L). However, only the prolyl and lysyl prodrugs exhibited enhanced uptake (2- to 8-fold) with HeLa/PEPT1 cells compared with HeLa cells, suggesting that the aspartyl prodrugs are PEPT1 inhibitors. The selective growth inhibition of Madine-Darby canine kidney (MDCK)/PEPT1 cells over MDCK cells by the prodrugs was consistent with the extent of their PEPT1-mediated transport. All ester prodrugs hydrolyzed to floxuridine fastest in Caco-2 cell and MDCK homogenates and slower in human plasma and were most chemically stable in pH 6.0 buffer. Prolyl and lysyl prodrugs were relatively less stable compared with aspartyl prodrugs in buffers and in cell homagenates. The results suggest that optimal design for targeted delivery would be possible by combining both stability and transport characteristics afforded by the. promoiety.