INHIBITION OF TUMOR-METASTASIS BY A SYNTHETIC-POLYMER CONTAINING A CELL-ADHESIVE RGDS PEPTIDE

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 mug) and liver metastasis of L5178Y-ML25 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 mug) 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 membrane Matrigel. Intermittent iv. administration of poly(CEMA-RGDS) after inoculation 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 of RGDS peptide with a polymeric carrier increases therapeutic potential to cancer metastasis, implying that RGDS-polymer conjugation may lead to the prolongation of antimetastatic action of RGDS peptide in vivo.