Repeated Intravenous Administration of Liposome-Encapsulated Muramyl Tripeptide-Phosphatidyl-Ethanolamine Diminishes Cytotoxic Potential of Subpopulations of Rat Liver Macrophages

Abstract

In this study we investigated the effects of repeated intravenous (i.v.) administration of liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (lipMTP-PE) on the antitumor functions of rat liver macrophages. Liver macrophage subtractions, differing in cell-size, were isolated by elutriation 24h after the final injection of liposomes and tested for cytotoxicity against radio-labeled C26 adenocarcinoma cells. Prolonged multiple i.v. injections of lipMTP-PE resulted in decreased tumoricidal activity in all but the small-sized subtraction, compared to a single injection.

Immunohistochemical staining of liver sections revealed that while the number of liver macrophages increased significantly after multiple lipMTP-PE injections, the expression of the la antigens on these cells decreased. Additionally, multiple lipMTP-PE treatment resulted in a reduced nitric oxide release in response to muramyl dipeptide in vitro, while incubation with another immunomodulator, lipopoly saccharide, resulted in substantial levels of NO secretion in all subtractions.

Taken together, these results demonstrate a diminished antitumor response and activated state of a significant part of the liver macrophage population after prolonged repeated administration of lipMTP-PE, and provide further insight in the behavior of the liver macrophage population during in vivo treatment with liposomal immunomodulators.