The macrophage as target or obstacle in liposome-based targeting strategies
Introduction
Macrophages can be found in all organs of the body. Monocytes, their direct precursors, are released in the circulation from the bone marrow (De Bruijn, 1997). Via the circulation, these monocytes immigrate into the organs where they differentiate in resident macrophages.
From an evolutionary point of view, macrophages form an ancient cell population, representing the main host defense mechanism before the development of the immune system. During evolution, these cells have also acquired important functions in the regulation of humoral and cellular immune reactions (serving as accessory cells for the induction of acquired immunity against particulate antigens), and in the control of various nonphagocytic cells that participate in immune responses. As a consequence, in mammals, macrophages are multifunctional cells (Van Rooijen et al., 1996a, Van Rooijen et al., 1996b).
The capability of macrophages to clear non-self (e.g. microorganisms) and altered-self (e.g. aged erythrocytes and apoptotic cells) particles represents an important mechanism of homeostasis. Such particles are ingested by macrophages and are consecutively digested with the aid of their large panel of lysosomal enzymes. This capability of macrophages can be advantageous when particulate drug-carriers, such as liposomes are to be targeted to macrophages, for instance when macrophages are the targets for delivery of liposome-encapsulated antimicrobial agents (Alving, 1988), macrophage-activators (Fidler, 1992) or antigens (Van Rooijen, 1995). However the same capability of macrophages is also responsible for removal of the bulk of most particulate targeting devices with a non-phagocytic destination, for example liposomes used as drug carriers (Hu et al., 1996) or adenovirus vectors used for gene transfer (Wolff et al., 1997), as well as of nonautologous grafted cells such as human cells grafted into severe combined immunodeficient (SCID) mice (Fraser et al., 1995). Correspondingly, it has been shown that transient suppression of macrophage functions by administration of liposome-encapsulated drugs improves the efficiency of such treatments (Van Rooijen et al., 1997). In general, in vivo applications of liposomes can be divided into two categories: those taking advantage of phagocytosis and those for which phagocytosis forms an obstacle on the way to success.
In the present contribution, the influence of macrophages on liposome-based targeting strategies will be reviewed.
Section snippets
Liposomes in the induction of immunity
Liposomes may be used for targeting of antigens to macrophages as a first step in the induction of immunity. However, liposomes may also be used to stimulate immunity by abrogation of the activity of suppressor macrophages.
Small soluble antigens such as serum albumins can be converted to particulate antigens by their association with liposomes. In vivo studies have shown that splenic phagocytic cells play a role in the induction of antibody responses against such liposomal antigens when
Approaches to prevent phagocytosis
Several particulate drug carrier devices have been proposed. Among these, liposomes may be considered the most versatile and promising drug delivery system (Gregoriadis, 1995). However, clearance by tissue macrophages prevents the bulk of all liposomes from reaching their targets. They are rapidly ingested and digested by macrophages and their encapsulated molecules may have an unwanted effect on macrophages and will be released in the circulation. Several modifications of the original liposome
Intravenous administration
Since liposomes are not able to cross the endothelial walls of blood capillaries, intravenously injected liposomes will target their contents only to those macrophage (sub)populations that are in direct contact with the blood circulation, i.e. to the Kupffer cells in the liver and to several subpopulations of splenic macrophages (Van Rooijen and Sanders, 1996). It has been demonstrated that intravenously injected liposome encapsulated drugs can also be targeted to macrophages in the bone-marrow
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