Serum-mediated recognition of liposomes by phagocytic cells of the reticuloendothelial system – The concept of tissue specificity

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Abstract

The mechanisms responsible for the clearance and recognition of intravenously injected liposomes by phagocytic cells of the reticuloendothelial system are presently not well understood. Here, we address a multiplicity of physicochemical and physiopathological factors which influence the clearance kinetics and tissue distribution of liposomes administered into the circulation. Emphasis is particularly drawn towards the concept of liposome–blood protein interaction and its role in liposome recognition by various phagocytes of the reticuloendothelial system.

Introduction

“The phagocyte won't eat the microbes unless the microbes are nicely buttered...that butter I call opsonin” [George Bernard Shaw, The Doctor's Dilemma]

A number of studies have illustrated that when liposomes are exposed to serum or plasma, they rapidly acquire a coating of proteinaceous molecules 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. This protein binding, which can be demonstrated by separating liposomes from serum or plasma incubations and then analyzing the liposome–protein complexes by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE), differs considerably in amount and in pattern depending on the dose, morphology (size and lamellarity), lipid composition, bilayer packing structure, and surface characteristics (charge, hydrophobicity/hydrophilicity, presence of polymers and ligands) of the vesicles 1, 3, 8, 10, 13, 14, 15, 16, 19. It is also possible that other proteinaceous molecules of functional significance bind loosely to the liposome surface and are lost in the routine separation procedures (ultracentrifugation and repeated washes, size exclusion chromatography, etc.) prior to SDS-PAGE analysis [13]. These liposome–blood protein interactions have a number of important ramifications for the subsequent behaviour of vesicles in vivo and for their use as drug and gene delivery systems. One aspect concerns the role of blood lipoproteins in liposome stability. For example, high-density lipoproteins (HDLs) in the plasma were found to remove phospholipid molecules from the bilayer of liposomes, leading to their disintegration and the loss of the entrapped drugs 4, 9, 11. The problem of HDL-induced stabilization of the liposomal bilayer has now been resolved by manipulating their composition, for instance by incorporation of excess cholesterol and/or by using phospholipids with a high-gel-liquid-crystalline transition temperature (Tc) [11]. Further discussion of this concept is beyond the scope of this article. Liposomes can also affect the blood-clotting cascade; a process which may lead to fibrin formation. This issue has been studied intensively by others and will not be discussed further 7, 8, 10, 12. Perhaps one of the most important aspects of liposome interaction with serum and plasma proteins concerns the potential for the acquisition of opsonic components, that is the adsorption of protein ligands capable of interacting with one or more receptors on the macrophage cell surface [17]. This process is thought to determine the rate and the site of liposome clearance from the blood and is dealt with here. It is not intended as a comprehensive review, but rather as an overview of the authors' own contribution to this field.

Section snippets

The mode of particle extraction from the blood by elements of the reticuloendothelial system (RES)

Numerous investigators in the past two decades have shown that the majority of particulate colloids and drug carriers in the form of emulsions, nanospheres, liposomes, etc. injected intravenously is retained by organs of the RES comprising the liver, the spleen, and the bone marrow 21, 22. Tissue fractionation studies have established that retention of colloidal particles in the liver is due primarily to their uptake by scavenging periportal and midzonal Kupffer cells (Fig. 1) 23, 24. Depending

Liposome opsonization and opsonophagocytosis

The mechanisms that govern the ways that liposomes are both detected as foreign particles in vivo and cleansed from the blood by phagocytic cells of the RES are presently unsolved. It is generally presumed that the important component of the detection process is the binding of proteins to the liposome surface 1, 3, 8, 10, 11, 13, 14, 15, 16, 17, 18, 19, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51. Contrary to such a belief, some investigators have pointed towards the existence of a

Species differences in liposome handling

Various observations highlighted species differences in the way that intravenously injected non-opsonized liposomes are handled and cleared from the blood by organs of the RES. One interesting example is the inclusion of negatively charged ganglioside GM1 into liposomal bilayer. In mice, GM1 dramatically reduced liposome (70–200 nm in diameter) recognition by Kupffer cells and, concomitantly, prolonged the liposome circulation time 79, 80. Following in vivo determinations and SDS-PAGE analysis,

The effect of liposomal cholesterol content

A number of investigators have demonstrated that in mice and rats intravenously injected cholesterol-free and cholesterol-containing liposomes (100–400 nm) are handled differently by liver, spleen, and bone marrow 85, 86, 87, 88. For example, intravenously injected cholesterol-free liposomes (composed of egg PC and DCP, mole ratio 7:1) are cleared more readily from the circulation than the cholesterol-poor liposomes (same formulation but containing 20 mol% cholesterol) and the cholesterol-poor

Conclusions

It is now clear that liposomes of differing morphology and surface characteristics attract different arrays of plasma proteins, the content and conformation of which may account for the different pattern in the rate and site of vesicle clearance from the blood. Because of the diversity and complexity associated with the dynamic process of in vivo liposome–protein interaction, it is difficult to assess and analyze the role of various blood opsonins in liposome recognition by phagocytes of the

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