Inhibition of Tumor Metastasis by a Synthetic Polymer Containing a Cell-Adhesive RGDS Peptide

ABSTRACT: A water soluble polymer containing cell adhesive Arg-Gly-Asp-Ser (RGDS) sequence, i.e., poly(carboxyethylmethacrylamide-RGDS) conjugate [poly(CEMA-RGDS)], was synthesized. Poly(CEMA-RGDS) inhibited lung metastasis of B16-BL6 melanoma cells in a dose-dependent manner (20-1000 μg) and liver metastasis of L5178YML25 lymphoma cells. A mixture of poly-(CEMA) and RGDS peptide or poly(CEMA) alone did not show any inhibitory effect on lung metastasis. The Gly-Arg-Gly-Asp-Ser (GRGDS) peptide required high doses (3000 μg) to obtain a sufficient antimetastatic effect. An in vitro study showed that poly(CEMA-RGDS) as well as RGDS + poly(CEMA) gave similar inhibition of B16-BL6 cell invasion into reconstituted basement mem-brane Matrigel. Intermittent i.v. administration of poly(CEMA-RGDS) after in-oculation with B16-BL6 cells caused significant inhibition of spontaneous lung metastasis as compared with the multiple administration of RGDS, poly-(CEMA) or untreated control. These results demonstrate that the conjugation *Author to whom correspondence should be addressed