Identification of proteins mediating clearance of liposomes using a liver perfusion system

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Abstract

The objective of this paper is to identify the principal blood components governing the fate of liposomes in blood circulation. Information based on an isolated perfused liver system in rats has revealed the central role of the complement system in enhancing the uptake of liposomes by the liver. A species difference was an important factor in determining the uptake mechanisms of liposomes by the liver. Limited evidence revealed the tendency that opsonin-dependent hepatic uptake is principal in rats, while opsonin-independent or dysopsonin-dependent uptake governs in mice, although there are some exceptions. These studies provide us with important information for understanding the uptake mechanisms of liposomes by the liver, and useful insights in predicting the in vivo disposition of liposomes in humans.

Introduction

The identification of serum opsonins for liposomes is essential in understanding the fate of liposomes in the blood circulation, because we note that opsonins play a central role in the uptake mechanisms of liposomes by cells such as Kupffer cells, endothelial cells in the liver, parenchymal cells and macrophages in spleen and bone marrow [1]. Several approaches have been applied to clarify this subject, including liposome–blood interaction in vitro 2, 3, 4, 5, cellular uptake by cultured cells 6, 7, 8, 9, isolated perfused liver 10, 11, 12, 13, 14, 15and in vivo studies 16, 17. The in vitro study on the interaction between liposomes and blood components identified the molecular species that determine the fate of liposomes in blood circulation. Chonn et al. postulated the PB-value as an index of protein binding to liposomes that can be a predictor of circulation half-life of liposomes in vivo [4], and the role of β2-glycoprotein I has been shown recently [17]. Cellular systems are effective in clarifying the uptake mechanisms of liposomes in cases, such as endocytosis/phagocytosis, receptor-mediated or not. The role of a `scavenger receptor' in the cellular uptake has been reported by several groups of investigators 7, 18, 19.

We have been using an isolated perfused liver system for the identification of serum opsonin and uptake mechanisms that are controlling the fate of liposomes in the blood circulation [20], and have found the role of the complement system in enhancing the hepatic uptake of liposomes via complement receptor-mediated phagocytosis for multilamellar vesicles (MLV) in rats 12, 13, 20. This system can provide reliable information on the hepatic uptake of liposomes, because it provides a condition similar to that in vivo, where capillary architecture, as well as inter-cellular environments, where polarity of cells is maintained [21]. In this review, we will focus on the hepatic uptake mechanisms of liposomes as determined in the isolated perfused liver system, in relation to those reported in cellular uptake studies and in vitro liposome–blood interaction studies.

Section snippets

Role of serum components in the hepatic uptake of liposomes

Sinusoids in the liver lobules consist of a unique type of lining of endothelial cells with small fenestrae of about 100 nm in size, the open fenestrae lacking a diaphragm [22]. An obvious filtration effect can be expected when particles of a smaller size than the fenestrae are carried into the liver. This anatomical barrier limits the uptake of large-diameter liposomes by parenchymal cells, however the exact threshold in the diameter of liposomes to be taken up by the liver is unknown. Red

Activation of complement system by liposomes

Activation of the complement system has been reported by several investigators for negatively charged and positively charged liposomes in human 2, 3, 26, rat 5, 27, 28and guinea pig [3]serum. Table 1 summarizes the liposomes that were shown to activate the complement system in serum or plasma, without introducing any specific ligands into liposomal membrane. Negatively charged liposomes 2, 3, 5, 26, 27, 28and positively charged liposomes 3, 27activated the complement system, whereas there was

Immunoglobulins

Human leukocytes express three classes of receptors for IgG, FcγRI, FcγRII and FcγRIII [54]. FcγRI binds to soluble monomeric IgG. The affinity of FcγRI for monomeric IgG is sufficiently high that the concentration of IgG in normal serum should yield nearly complete occupation of this receptor. However, FcγRI retains the ability to recognize IgG-coated particles in the presence of serum. It is likely that an IgG-coated particle presents many Fc portions, and this multi-valency may provide the

Species differences

Inclusion of GM1 into liposome membrane was shown to increase the circulation time of liposomes in mice [39], the first report by Allen and Chonn which develops the idea of a long circulating liposome. However, this effect was species dependent in that a rapid disappearance of GM1-containing liposomes has been shown in rats [38]. Liu et al. extensively investigated species differences in the hepatic uptake of liposomes [14]. They have used perfused rat and mouse liver to investigate the serum

Conclusions

The effect of serum on the hepatic uptake mechanisms of liposomes by the liver is summarized in Table 4. The complement system was shown to play an important role in enhancing the uptake of liposomes composed of negatively charged, both saturated and unsaturated, and a relatively large size of liposomes under the isolated perfused rat liver. A remarkable species difference was also found between animal species. In mice, a serum-independent or dysopsonin- but not opsonin-dependent mechanism

Notation

C3the third component of complement system
C3bfragment of C3
C5the fifth component of complement system
C5afragment of C5
CR1complement receptor type 1
CR3complement receptor type 3
CHcholesterol
CHEcholesteryl hexadecyl ether
CLhhepatic uptake clearance
CLtottotal body clearance
DCPdicetylphosphate
DMPCdimyristoyl phosphatidylcholine
DOPCdioleoyl phosphatidylcholine
DOPEdioleoyl phosphatidylethanolamine
DPPGdipalmitoyl phosphatidylglycerol
DSPCdistearoyl phosphatidylcholine
EPCegg phosphatidylcholine
GM1

Acknowledgements

The authors would like to express our appreciation to Professor M. Naito of his kind instruction for the electron microscopy of liposomal uptake by the liver. We would also like to thank Mr. Rick Cogley for his helpful advice in writing the English manuscript.

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    Present address: Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

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