Liposomes: bags of challenge.

The major problem in chemotherapy is the targetting of drugs to restricted anatomical sites and specific target cells. Many drugs produce side effects, are toxic to normal tissues and are often prematurely inactivated or excreted. To overcome such difficulties, several forms of drug carriers have been described and tested in animals, and on some occasions in man (Ryman & Tyrrell, 1980; Gregoriadis, 1981). Among these drug carriers, liposomes, being versatile non-toxic and biodegradable, have received considerable attention as carriers of various drugs such as antitumour agents, antibiotics, hormones, proteins and DNA (Ryman & Tyrrell, 1980; Patel & Ryman, 1981). The term 'liposome' was first proposed by Bangham et al. (1965). They consist of one or more concentric lipid bilayers enclosing an equal number of aqueous compartments in which water-soluble substances can be entrapped. Various techniques have been described to prepare liposomes of different sizes and characteristics (Ryman & Tyrrell, 1979; Szoka & Papahadjopoulos, 1981). Liposomes have been administered by various routes (topically, parenterally, by inhalation and orally), and this subject has been reviewed by Patel & Ryman (1981). Subcutaneously, intraperitoneally and intramuscularly injected liposomes are drained from the site of injection into the circulation via the lymphatics. In lymph, some liposomes are degraded and some reach the circulation intact. Thus liposomes can be used via these routes for (i) delivery of drugs to lymph nodes (Khato et al., 1982) and (ii) detection of metastatic spread in lymph nodes by encapsulating lymphoscintigraphic material (Osborne et al., 1980). Orally administered liposomes can survive digestion in the stomach, although they are degraded in the intestine. However, they protect the entrapped proteins from proteolytic digestion and facilitate their absorption from the gastrointestinal tract (Patel & Ryman, 1981). Intravenously injected liposomes are rapidly sequestered by mononuclear phagocytes of the reticuloendothelial system. Their blood clearance rate depends on the charge, size and lipid composition of liposomes. In the circulation, their properties such as permeability, size and surface charge are altered rapidly, and they can be broken down by lipoproteins, circulating phospholipases or by complements, (Patel & Ryman, 1981). By selecting the composition of liposomes, the stability of the vesicles in the circulation can be improved (Gregoriadis et al., 1983). In blood, liposomes may be taken by circulating leucocytes and monocytes and interact with platelets and endothelial cells lining the capillaries. Liposomes do not escape from the circulation to tissues other than those with discontinuous endothelial lining to their capillaries, i.e. liver and spleen. In these tissues, phagocytic cells of the reticuloendothelial system remove the vesicles which are degraded by lysosomes. The fact that liposomes are predominantly taken up by the tissues rich in reticuloendothelial cells limits the use of liposomes in cancer chemotherapy, as cytotoxic drugs in liposomes will destroy cells of liver and spleen. Cancer patients require a healthy reticuloendothelial system to clear the toxic products of cancer cells and control the spread of the disease to normal tissue. Furthermore, owing to the lack of penetration of intact liposomes through capillary endothelial barriers, liposomes may not reach many diseased tissues. These factors will also limit the use of antibodylabelled liposomes to target to specific cells in vivo. Thus the original hope that the liposome would present a new form of drug carrier with greater selectivity and the potential for targetting to specific tissues has not been, and may never be, realized. However, it seems that passive targetting, the natural 'homing' of liposomes to elements of the reticuloendothelial system, may be exploited in several ways.