抄録
L-arginine-L-glycine-L-aspartic acid (RGD) sequence, originally found in fibronectin, one of main component of extracellular matrices, is known as a ligand to some adhesion molecules. Since the interaction of metastatic tumor cells with target endothelium and extracellular matrices under it, is important for establishment of blood-borne metastasis, analogs of the peptide have been developed for the suppression of tumor metastasis. In fact, some synthetic peptides having the RGD sequence have been found to decrease metastatic colonization. To enhance the metastasis-suppressing efficacy of these analogs, we attempted to stabilize and to prolong the circulation time of these analogs by liposomalization. Various structures of hydrophobizcd-RGD analogs (lipophilic antimetastatic peptides, LAPs) were synthesized, and incorporated into liposomes. Liposomes composed of distearoylphosphatidyl-choline, cholesterol, dipalmitoylphosphatidylglycerol and LAPs were injected intravenously with B16BL6 murine melanoma cells into mice. Liposomal RGD (0.6 μmol of the analog equivalent to ca. 200 μg RGD peptides) inhibited lung colonization up to 76%. This dose is an order of magnitude lower than that for comparable inhibition reported for free RGD. Multi-dose administration of LAP-liposomes (0.15 μmol of the analog equivalent to ca. 50 μg RGD peptides) also inhibited the spontaneous lung metastasis of cells from a primary tumorsite of B16BL6 cells subcutaneously implanted into the footpad of mice. In conclusion, liposomal RGD may be useful for the suppresion of tumor metastasis.
