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Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Gordon L. Amidon, Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065. Phone: 734-764-2440; Fax: 734-763-6423. E-mail: glamidon{at}umich.edu

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 PEPT1 (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 homogenates. The results suggest that optimal design for targeted delivery would be possible by combining both stability and transport characteristics afforded by the promoiety.

Key Words: floxuridine • amino acid ester prodrugs • PEPT1 transport • activation • targeting

Grant support: NIH grant R01-GM37188.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: B.S. Vig is currently at the Exploratory Biopharmaceutics and Stability, Drug Delivery Enablement, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., New Brunswick, NJ 08502.

Received 10/29/04; revised 1/25/05; accepted 2/15/05.