Abstract
A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5′-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 – 2.3 mM in Caco-2 and 2.0 – 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 – 5.31 x 10-6 cm/sec) and floxuridine (0.48 x 10-6 cm/sec) were much higher than that of 5-FU (0.038 x 10-6 cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.
Highlights
The anti-metabolites 5-fluorouracil (5-FU) and floxuridine (5-fluoro-2'-deoxyuridine) continue to be mainstay drugs for colorectal cancer treatment after 50 years [1]
It has been suggested that the biphenyl hydrolase-like protein recently identified as being responsible for hydrolysis of the prodrug valacyclovir (VACVase), might be involved in the activation of other amino acid prodrugs [11]
The antiviral drug valacyclovir is an example of a successful amino acid ester prodrug strategy [34]
Summary
The anti-metabolites 5-fluorouracil (5-FU) and floxuridine (5-fluoro-2'-deoxyuridine) continue to be mainstay drugs for colorectal cancer treatment after 50 years [1]. Amino acid ester prodrugs of floxuridine and the antiviral agent acyclovir have been shown to be substrates of the PEPT1 transporter [14, 15]. The experiments concerning prodrug stability were performed at 37°C in pH 7.4 phosphate buffers and Caco-2, AsPC-1, and MDCK cell homogenates.
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