A novel polymeric spermine conjugate inhibits polyamine transport in pulmonary artery smooth muscle cells.

The polyamines putrescine, spermidine and spermine (SPM) are low molecular weight organic cations that play essential intracellular regulatory roles in cell growth and differentiation. Whereas both de novo polyamine synthesis and transmembrane transport regulate cell polyamine contents, exploitation of pathways as pharmacologic targets has been limited by the lack of agents which specifically block polyamine transport. We now report the synthesis and biologic activity of novel polymeric glutaraldehyde conjugates of putrescine, spermidine and SPM which act at the cell membrane to inhibit polyamine uptake in cultured bovine pulmonary artery smooth muscle cells. Each conjugate caused dose-related inhibition of [14C]polyamine transport in pulmonary artery smooth muscle cells with the polymeric SPM conjugate being most effective in inhibiting the uptake of all three polyamines. Polymeric SPM failed to impair uptake of neutral or charged amino acids or to associate with pulmonary artery smooth muscle cells in a temperature-dependent manner. The polymeric SPM conjugate caused substantial decreases in cell polyamine contents which were associated with concentration-dependent cytotoxicity. Spectroscopic analyses of the polymeric SPM conjugate indicated that its molecular weight was 25 +/- 0.5 kDa, which is equivalent to approximately 90 monomeric--HN(CH2)3NH(CH2)4NH(CH2)3NH(CH2)5--units. These findings indicate that reduced polymeric glutaraldehyde conjugates of the polyamines may function as specific inhibitors of polyamine transport and thus provide a basis for examination of polyamine transport as a pharmacologic target in disorders characterized by dysregulated cell growth and differentiation.