Synthesis of macromolecular conjugates of a urokinase inhibitor: Amiloride

Amiloride is a potent inhibitor of a urokinase type plasminogen activator w hich is involved in the invasive process of cancer cells leading to the ini tiation of metastasis. Synthesis, characterization and in vitro tests of fo ur macromolecular conjugates of Amiloride are presented. One of them is a d egradable derivative, HPPMA-Gly-D,L-Phe-Leu-Gly-amiloride. In this case the in vitro release of Amiloride was monitored. Other conjugates are stable c ontaining a new amiloride derivative, 6-aminohexyl amiloride [AHA], coupled to different polymeric carriers: a branched polypeptide, poly-[Lys(AcGlu(1 .0)-D,L-Ala(4.5))] [AcEAK], poly-[N-(2-hydroxy propyl) metacrylamide] [HPMA ] and poly-1-vinyl-2-pyrrolidone-co-maleic acid] [NVP MA]. Inhibition of uP A, plasminogen activation and proteinases secreted by cancer cells was meas ured as well as basement membrane degradation in vitro. Each amiloride AHA and the corresponding conjugates retained their activity in these experimen ts.