1998 Volume 13 Issue 6 Pages 429-434
In the present study, we evaluated the lung metastasis inhibitory effect and optimal dosage of N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys), a lipophilic derivative of muramyl dipeptide (MDP) acting as a macrophage activator, in hamsters bearing osteosarcoma. MDP-Lys was administered either as a solution or liposomal preparation (multilamellar, about 2 μm of diameter). The time course of lung metastatic rates after transplantation of osteosarcoma to the lower extremity was estimated macroscopically and pathologically for 7 weeks. In this study, the extremity was amputated 3 weeks after transplantation. The lung metastatic rates observed were 0%, 10%, 50%, 70%, and 100%, 1, 2, 3, 5, and 7 weeks after transplantation, respectively. Based on these results, the inhibitory effect of MDP-Lys given as a solution or multilameliar liposome on lung metastasis was evaluated 7 weeks after transplantation. Hamsters, which were transplanted osteosarcoma and their extremity were amputated 3 weeks after transplantation, were divided into 3 groups. Treatments with MDP-Lys were carried out for 4 weeks after the amputation. The first group received free MDP-Lys subcutaneously as a solution (0.5, 5, 50 μg/day), the second group received liposomal MDP-Lys (2 or 20 μg, twice/week), and the third group received only empty liposome (twice/week) intravenously as a control. The inhibitory effects of MDP-Lys on lung metastasis were observed in the following two treatment groups : MDP-Lys given as a solution (50 μg/day) reduced the lung metastatic rate to 54.5%, and liposomal MDP-Lys (20 μg, twice/week) reduced to 60%. Thus, liposomal MDP-Lys showed a similar inhibitory rate to that given as a solution at a far lower dose (40 μg vs 350 μg/week). Considering that hamsters had lung metastasis at a rate of 50% before the treatment, above treatments with MDP-Lys inhibited the metastasis almost completely. The optimal dosage of MDP-Lys given as a solution would be more than 50 μg/day, and that of MDP-Lys given as a liposome would be more than 20 μg (twice per week). The greater efficacy of liposomal delivery would be due to the longer drug retention in the body. To confirm it, fluorescein was given intravenously either as a solution or multilamellar liposome (same size and composition to that of MDP-Lys), and the time course of fluorescein amount retained in the lung, liver and serum were determined. Fluorescein given as a solution was almost disappeared from the lung, liver and serum within 12 hrs. In contrast, fluorescein given as a liposome was retained in the body for about 72 hrs. Thus, it would be concluded that the greater lung metastasis inhibitory effect of liposomal MDP-Lys than that of solution would he due to the long drug retention in the body, especially in the lung.
