Carbamylation Decreases the Cytotoxicity but not the Drug-Carrier Properties of Polylysines

The charge density of Poly(D-lysine) was reduced by the carbamylation of the lysyl residues with potassium cyanate. A decrease in the charge density of poly(D-lysine) by 25% and 50% reduced the cytotoxicity of the ligand to cultured L929 cells by a 5-, and a 20 to 25-fold level, respectively, as estimated by using either the viability or the protein assay. The uptake of cyanate-modified poly(D-lysine) ligands in cultured L929 cells was not reduced, while the uptake of poly(D-lysine)/Heparin complex was reduced by 80%, as compared to that of unmodified poly(D-lysine). The in vivo biodistribution of cyanate-modified poly(D-lysine) ligands in the lungs and the liver of mice was not altered in comparison to that of unmodified poly(D-lysine), whereas the poly(D-lysine)/Heparin complex was only accumulated in the liver but not in the lungs. The data in this paper indicate that a 50% decrease in the positive charge density of poly(D-lysine) reduces the toxicity, but not the carrier potential of this polycationic ligand.