Development of anti-metastatic agents related to the early event of metastasis : screened by novel imaging thchnique.

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Metastasis is established by a complex cascade of activities, and adhesion of tumor cells to endothelia or to extracellular matrix is one of the critical steps in the metastatic cascade. Therefore, agents that suppress such interaction may serve as anti-metastatic drugs. We previously established a non-invasive method to determine metastatic tumor cell trafficking by use of positron emission tomography (PET). In this method, positron-labeled metastatic cells are injected into bloodstream to determine tumor cell biodistribution in real-time from immediately after injection in a living animal. In here, to elucidate the involvement of cellular surface adhesion molecules in metastatic process, we investigated the effect of liposomalized sialyl Lewis X (sLe^x) as well as RGD-related peptide on the trafficking of B16BL6 melanoma cells and on metastatic potential. The trafficking of the cells after injection into tail vein was highly affected by liposomal sLe^x, but only little by RGD-related peptide, suggesting adhesion of metastatic cells to the target is initially mediated via selectin, and integrin-mediated adhesion may occur the later stages. Furthermore, liposomal sLe^x suppressed experimental metastasis suggesting that adhesion via selectin is important step for metastasis. Next to enhance the metastasis-suppressing efficacy, liposomalizaton of RGD was attempted, since RGD-related peptides have been found to suppress metastasis. Various structures of RGD analogs grafted to hydrophobic groups were systhesized and then incorporated into liposomes. Some of liposomalized RGD markedly inhibited lung colonization at the concentration of an order of magnitude lower than that for comparable inhibition reported for free RGD.The present study indicate that liposomal application is useful for both clarifying metastasis mechanism and development of anti-metastatic pharmaceutics.