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 pol y(CEMA-RGDS)!, was synthesized. Poly(CEMA-RGDS) inhibited lung metasta sis 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 inhibitor y effect on lung metastasis. The Gly-Arg-Gly-Asp-Ser (GRGDS) peptide r equired high doses (3000 mug) to obtain a sufficient antimetastatic ef fect. An in vitro study showed that poly(CEMA-RGDS) as well as RGDS poly(CEMA) gave similar inhibition of B16-BL6 cell invasion into recon stituted basement membrane Matrigel. Intermittent iv. administration o f poly(CEMA-RGDS) after inoculation with B16-BL6 cells caused signific ant inhibition of spontaneous lung metastasis as compared with the mul tiple administration of RGDS, poly(CEMA) or untreated control. These r esults demonstrate that the conjugation of RGDS peptide with a polymer ic carrier increases therapeutic potential to cancer metastasis, imply ing that RGDS-polymer conjugation may lead to the prolongation of anti metastatic action of RGDS peptide in vivo.