The macrophage as target or obstacle in liposome-based targeting strategies

Abstract

Macrophages can be found in all organs of the body. For that reason, the majority of liposomes, intended for drug- or antigen-targeting in vivo, will find macrophages on their way. Phagocytosis of the liposomes followed by disruption of their phospholipid bilayers and release of the entrapped molecules will be the consequence. This capability of macrophages may be an advantage when these cells themselves are forming the targets of the liposomes. However in most cases, the activity of macrophages has to be considered an obstacle for liposome-based targeting strategies. The positive and negative effects of macrophages on liposomes as drug- and antigen-carriers will be discussed.

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.