Containing Macrophage Activators Metastases following Intravenous Injection of Liposomes Involvement of Macrophages in the Eradication of Established

Liposomes containing encapsulated lymphokines or muramyl dipeptide (MDP), when injected i.v. into C57BL/6 mice, pro duce significant destruction of established lung and lymph node métastasesfrom a s.c. highly metastatic B16-BL6 mela noma. We present evidence that eradication of the métastases is mediated by the activation of host macrophages to the tumoricidal state. Results from three separate types of experi ments support this conclusion, (a) When macrophage-activating agents such as lymphokines or MDP were delivered in liposomes that were not efficiently retained in the lung, little or no activation of lung macrophages was observed, and growth of métastases was unaltered, (o) Eradication of métastases was not observed when tumor-bearing animals were treated with agents that impaired macrophage function (e.g., silica, carrageenan, hyperchlorinated drinking water) prior to sys temic therapy with liposome-encapsulated lymphokines or liposome-encapsulated MDP. (c) Macrophages activated in vitro by liposome-encapsulated MDP and then injected i.v. into mice bearing experimental lung métastases also significantly in hibited lung métastases. These results suggest that the aug mented host response against pulmonary and lymph node métastasesgenerated by the systemic administration of lipo some-encapsulated lymphokines or MDP is mediated via acti vated cytotoxic macrophages.