LIPOSOMAL ARG-GLY-ASP ANALOGS EFFECTIVELY INHIBIT METASTATIC B16 MELANOMA COLONIZATION IN MURINE LUNGS

Analogs of a synthetic peptide having the L-arginine-L-glycine-L-aspar tic acid (RGD) sequence have been found to decrease metastatic coloniz ation. To enhance the metastasis-suppressing efficacy of these analogs , we sought to stabilize these analogs and to prolong their circulatio n time by incorporating them into a liposomal formulation. Various str uctures of RGD analogs grafted to hydrophobic groups were synthesized and then incorporated into liposomes. Liposomes composed of distearoyl phosphatidyicholine, cholesterol, dipalmitoylphosphatidylglycerol and appropriate RGD analogs were injected intravenously along with B16BL6 murine melanoma cells into mice. Liposomal RGD (0.6 mu mol of the anal og equivalent to ca. 200 mu g RGD peptides) inhibited lung colonizatio n up to 76%. This dose is an order of magnitude lower than that for co mparable inhibition reported for free RGD. Multi-dose administration o f liposomal RGD (0.15 mu mol of the analog) also inhibited the spontan eous lung metastasis of cells from a primary tumor site of B16BL6 cell s subcutaneously implanted into the footpad of mice. Taken together, o ur data indicate that liposomal RGD may serve as a useful anti-metasta tic agent.