Ultrastructural and Freeze Fracture Localization of Multilamellar Liposomes Containing a Lipophilic Cisplatin Analogue in Normal Tissues and Liver Metastases of M5076 Reticulosarcoma

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Abstract
The tissue localization of multilamellar vesicles (MLV) (size 0.5 -5.0 μm) composed of dimyristoylphosphatidyl choline (DMPC) and dimyristoylphosphatidyl glycerol (DMPG) (molar ratio 7:3) containing a lipophilic cisplatin analogue (NDDP) was studied in mice by freeze fracture (FF) and transmission electron microscopy (TEM). Liposomes were observed within cytoplasmic vacuoles of hepatocytes and Kupffer cells in normal mice as early as 5 minutes after intravenous (iv) administration of MLV-NDDP. Liposomes within hepatocytes were more numerous but smaller in diameter (0.5-2.0 μm) than those within Kupffer cells (2.0-4.0 μm). In normal lung examined by FF or TEM at 5 minutes after MLV-NDDP administration, liposomes were only observed in the intravascular space. Liposomes could not be identified within Type I or II pneumocytes nor within the alveolar space. Two hours after iv administration, the distribution within the liver showed an increased number of liposomes in the hepatocytes with some evidence of liposome decomposition. The distribution in the lung was virtually identical to that observed at 5 minutes. The pattern of tissue localization within lung and liver of empty MLV 5 minutes and 2 hours after iv administration was identical to that of MLV-NDDP. In mice bearing gross liver metastases of M5076 reticulosarcoma, liposomes were present in the cytoplasm of tumor cells as well as normal cells 5 minutes and 2 hours after the iv administration of MLV-NDDP. These studies suggest that MLV composed of DMPC and DMPG containing NDDP are able to cross the liver sinusoidal capillaries and gain access to both hepatocytes from normal liver and malignant cells of M5076 reticulosarcoma from liver metastases.