Pharmaceutical Research

, Volume 28, Issue 10, pp 2575–2588 | Cite as

Potential of Amino Acid/Dipeptide Monoester Prodrugs of Floxuridine in Facilitating Enhanced Delivery of Active Drug to Interior Sites of Tumors: A Two-Tier Monolayer In Vitro Study

  • Yasuhiro Tsume
  • John M. Hilfinger
  • Gordon L. Amidon
Research Paper



To evaluate the advantages of amino acid/dipeptide monoester prodrugs for cancer treatments by assessing the uptake and cytotoxic effects of floxuridine prodrugs in a secondary cancer cell monolayer following permeation across a primary cancer cell monolayer.


The first Capan-2 monolayer was grown on membrane transwell inserts; the second monolayer was grown at the bottom of a plate. The permeation of floxuridine and its prodrugs across the first monolayer and the uptake and cell proliferation assay on secondary layer were sequentially determined.


All floxuridine prodrugs exhibited greater permeation across the first Capan-2 monolayer than the parent drug. The correlation between uptake and growth inhibition in the second monolayer with intact prodrug permeating the first monolayer suggests that permeability and enzymatic stability are essential for sustained action of prodrugs in deeper layers of tumors. The correlation of uptake and growth inhibition were vastly superior for dipeptide prodrugs to those obtained with mono amino acid prodrugs.


Although a tentative general overall correlation between intact prodrug and uptake or cytotoxic action was obtained, it appears that a mixture of floxuridine prodrugs with varying beneficial characteristics may be more effective in treating tumors.


antiproliferative action Capan-2 pancreatic cancer cells in vitro tumor model mono amino acid and dipeptide monoester floxuridine prodrugs permeation and bioactivation prodrug cocktail two-tier Capan-2 monolayer two-tier Capan-2 pancreatic cancer monolayer 



We thank Dr. Wei Shen for his expertise with prodrug purification. This work was supported by grants NIGMD-2R01GM037188.


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Yasuhiro Tsume
    • 1
  • John M. Hilfinger
    • 2
  • Gordon L. Amidon
    • 1
  1. 1.Department of Pharmaceutical ScienceUniversity of MichiganAnn ArborUSA
  2. 2.TSRL, Inc.Ann ArborUSA

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