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Involvement of Macrophages in the Eradication of Established Metastases following Intravenous Injection of Liposomes Containing Macrophage Activators¹

Cancer Metastasis and Treatment Laboratory, NCI-Frederick Cancer Research Facility, Frederick, Maryland 21701 [I. J. F., Z. B., W. E. F.]; Smith, Kline and French Laboratories, Philadelphia, Pennsylvania 19101 [R. K., P. B., G. P.]; and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 [G. P.]

Liposomes containing encapsulated lymphokines or muramyl dipeptide (MDP), when injected i.v. into C57BL/6 mice, produce significant destruction of established lung and lymph node metastases from a s.c. highly metastatic B16-BL6 melanoma. We present evidence that eradication of the metastases is mediated by the activation of host macrophages to the tumoricidal state. Results from three separate types of experiments 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 metastases was unaltered. (b) Eradication of metastases was not observed when tumor-bearing animals were treated with agents that impaired macrophage function (e.g., silica, carrageenan, hyperchlorinated drinking water) prior to systemic 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 metastases also significantly inhibited lung metastases. These results suggest that the augmented host response against pulmonary and lymph node metastases generated by the systemic administration of liposome-encapsulated lymphokines or MDP is mediated via activated cytotoxic macrophages.

¹ Research sponsored by the National Cancer Institute, Department of Health and Human Services, under Contract NO1-C0-75380 with Litton Bionetics, Inc. and United States Public Health Service Grants CA18260 and CA30192. The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government.

² To whom requests for reprints should be addressed.

Received 7/27/81. Accepted 10/26/81.

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