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  • Title: Design of liposomes to improve delivery of macrophage-augmenting agents to alveolar macrophages.
    Author: Fidler IJ, Raz A, Fogler WE, Kirsh R, Bugelski P, Poste G.
    Journal: Cancer Res; 1980 Dec; 40(12):4460-6. PubMed ID: 7002293.
    Abstract:
    Factors affecting the localization of liposomes injected i.v. in the lung have been studied to identify the optimal type of liposome for delivery of macrophage-activating agents to the lung to augment the tumoricidal activity of alveolar macrophages (AM). Comparison of pulmonary retention of liposomes of differing size, surface charge, and composition following i.v. injection into inbred mice revealed that large multilamellar (MLV) and reversed-phase-evaporation (REV) liposomes are arrested in the lung more efficiently than are small unilamellar liposomes of identical lipid composition. MLV and REV containing negatively charged amphiphiles arrest in the lung more efficiently than do neutral MLV's or REV's or MULV's and REV's containing positively charged amphiphiles. Comparison of the ability of liposomes containing a variety of negatively charged amphiphiles to localize in the lung established that optimal localization was achieved using MLV and REV prepared from phosphatidylserine (PS) and phosphatidylcholine (PC) (3:7 mol ratio) or PS:PC:lysolecithin (4.95:4.95:0.1 mol ratio). The proportion of these liposomes retained in the lung after i.v. injection was constant over a wide dose range (0.02 to 20 mumol phospholipid per mouse), but hemodilution due to i.v. inoculation of liposomes in volumes exceeding 0.2 ml reduced retention in the lung. Uptake of liposomes by AM was demonstrated by showing that i.v. injection of PS:PC MLV liposomes containing fluorescein-labeled bovine serum albumin resulted in localization of fluorescence within AM recovered by pulmonary lavage. Similarly, AM recovered after i.v. injection of PS:PC MLV liposomes containing lymphokine preparations rich in macrophage-activating factor (MAF) activity exhibited tumoricidal activity. In contrast, macrophages recovered from control animals given injections of unencapsulated MAF or liposomes containing lymphocyte supernatants without MAF activity were devoid of cytotoxic activity. Neutral (PC) MLV liposomes containing MAF, which show only very limited retention in the lung, were ineffective in activating AM in situ. We conclude that negatively charged MLV liposomes (PS:PC, 3:7 mol ratio) localize efficiently in the lung and that macrophage-activating agents encapsulated within such liposomes can successfully activate lung macrophages in situ.
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