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The Role of Plasma Membrane Receptors and the Kinetics of Macrophage Activation by Lymphokines Encapsulated in Liposomes¹

Cancer Metastasis and Treatment Laboratory, National Cancer Institute Frederick Cancer Research Center, Frederick, Maryland 21701 [I. J. F., A. R., W. E. F., L. C. H.], and Department of Experimental Pathology, Roswell Park Memorial Institute, Buffalo, New York 14263 [G. P.]

The kinetics of activation of tumoricidal functions in mouse macrophages incubated with macrophage-activating factors (MAF) released by mitogen-stimulated lymphocytes (free MAF) and MAF encapsulated within liposomes (liposome-MAF) have been compared. Development of tumoricidal activity requires incubation of macrophages with free or liposome-encapsulated MAF for a minimum of 4 hr. Macrophages incubated with MAF for 4 hr were not cytotoxic when tumor target cells were added immediately after removal of MAF, but they were highly cytotoxic when allowed to complete a "lag" phase before being exposed to tumor cells. The duration of the lag phase varied with different activation protocols. The level of cytotoxic activity induced by liposome-encapsulated MAF was consistently higher than that obtained with free MAF. Studies using inhibitors of endocytosis demonstrated that internalization of the liposome carrier is required for activation by liposome-MAF and that activation does not result from MAF leaking from liposomes and binding to MAF receptors on either the plasma membrane or the membrane of endocytic vesicles. Comparison of the efficiency of macrophage activation by MAF encapsulated in liposomes of differing internal volume revealed that large multilamellar and large unioligolamellar liposomes were more efficient in activating peritoneal exudate macrophages than were small unilamellar liposomes. Measurement of the volume of liposome contents internalized by macrophages from these three types of liposomes revealed that maximum cytotoxicity required internalization of a given volume of MAF-containing lymphocyte supernatants, after which no further increase in cytotoxicity occurred.

¹ Research sponsored by National Cancer Institute Contract NO1-CO-75380 with Litton Bionetics, Inc., and NIH Core Support Grant CA 17609 to Roswell Park Memorial Institute.

² To whom requests for reprints should be addressed.

³ Recipient of USPHS Research Grants CA 13393 and CA 18260.

Received 3/20/80. Accepted 10/16/80.