caa a22 4500 445313242 CHVBK 20180317142637.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s11095-011-0485-7 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0485-7 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 [Elektronische Daten] [Yasuhiro Tsume, John Hilfinger, Gordon Amidon] ABSTRACT: Purpose: 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. Methods: 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. Results: 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. Conclusions: 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. Springer Science+Business Media, LLC, 2011 antiproliferative action nationallicence Capan-2 pancreatic cancer cells nationallicence in vitro tumor model nationallicence mono amino acid and dipeptide monoester floxuridine prodrugs nationallicence permeation and bioactivation nationallicence prodrug cocktail nationallicence two-tier Capan-2 monolayer nationallicence two-tier Capan-2 pancreatic cancer monolayer nationallicence Tsume Yasuhiro Department of Pharmaceutical Science, University of Michigan, 48109, Ann Arbor, Michigan, USA aut Hilfinger John TSRL, Inc., 48108, Ann Arbor, Michigan, USA aut Amidon Gordon Department of Pharmaceutical Science, University of Michigan, 48109, Ann Arbor, Michigan, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2575-2588 0724-8741 28:10<2575 2011 28 11095 https://doi.org/10.1007/s11095-011-0485-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0485-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tsume Yasuhiro Department of Pharmaceutical Science, University of Michigan, 48109, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Hilfinger John TSRL, Inc., 48108, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Amidon Gordon Department of Pharmaceutical Science, University of Michigan, 48109, Ann Arbor, Michigan, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2575-2588 0724-8741 28:10<2575 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer