Biochimica et Biophysica Acta (BBA) - Biomembranes
Influence of glycolipids on immune reactions of phospholipid antigens in liposomes
Abstract
Complement-dependent immune damage to liposomes mediated by a murine monoclonal antibody to the liposomal bilayer was completely inhibited by ceramide tetrasaccharide (globoside) at an 8% concentration in the liposomes. Lower concentrations of globoside, or higher concentrations of ceramide tri-, di-, or monohexoside, were not inhibitory. At a globoside concentration of 5.8%, inhibition of the monoclonal antibody activity was reduced and inhibition was related to antibody concentration; but at 2% globoside, suppression of antibody activity was not observed at all. Analysis of space-filling models revealed that at 8% globoside the distance between adjacent tetrasaccharides of globoside approached the dimensions of the antigen-binding end of a 7S immunoglobulin molecule. We therefore propose that globoside, and perhaps other glycolipids, can exert steric hindrance to the binding of extracellular proteins to nonglycolipid constituents of the lipid bilayer. We conclude that microheterogeneity among polar groups of glycolipids may be a novel mechanism for allowing selective access of proteins to phospholipids on the lipid bilayer.
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Carbohydrate-mediated liposomal targeting and drug delivery
1994, Advanced Drug Delivery ReviewsThe surface of the cell is rich in carbohydrate moieties attached to both membrane glycolipids and glycoproteins. These oligosaccharides constitute potential recognition sites for carbohydrate-mediated interactions between cells and drug carriers bearing suitable site-directing molecules. Liposomes constitute a potentially valuable type of drug carrier. The ability to incorporate various site-binding molecules into the liposomal surface leads to a wide range of delivery systems based on carbohydrate-mediated interactions. In this review the types of recognition site on the surface of mammalian cells are considered with regard to both their chemical composition and the physical constraints which might effect their recognition by drug carriers with site-directing groups. Of particular current interest are the cell surface carbohydrate-binding proteins (lectins) which have yet to be fully exploited as recognition sites for carrier systems. Potential liposomal drug carriers have been considered under a range of headings: glycolipid-bearing, glycoprotein-bearing, virus spike glycoprotein-bearing (the so-called ‘virosomes’), antibody-bearing immunoliposomes, lipopolysaccharide, polysaccharide-bearing and lectin-bearing. Examples of the applications of these various types of liposomes and their targeting to recognition sites on cells are reviewed. It is clear that while these systems could be of considerable value for the targeting of drugs, a great deal more work has been reported on the preparation, control and targeting of liposomal systems involving carbohydrate-mediated interactions than has been reported on their actual use for the delivery of specific drugs to cells. Carbohydrate-mediated drug delivery using liposomes is a very sophisticated approach which will not be easy to exploit without very considerable investment. At present, much of the technology required to exploit carbohydrate-mediated interactions in drug delivery is available and future progress will depend on a determination to use this technology to develop drug-carrying liposomal systems. The diversity of potential systems is large and the choice of liposomal system for targeting a drug to a particular cell type will have to be determined by balancing specificity of the liposomal carrier against ease of production.
Immunologic aspects of liposomes: presentation and processing of liposomal protein and phospholipid antigens
1992, BBA - Reviews on BiomembranesGloboside with spin-labelled fatty acid: bilayer lateral distribution and immune recognition
1988, BBA - BiomembranesWe have critically addressed the question of lateral distribution of glycolpids in bilayer membranes, and the effect of glycolipid fatty acid chain length upon such distribution. For this purpose we synthesised the complex neutral glycosphingolipid, globoside, with spin-labelled fatty acid. Base hydrolysis to remove the natural fatty acid was found to deacetylate the GalNAc residue concomitantly, necessitating application of the synthetic route described for gangliosides by Neuenhofer et al. (Biochemistry 24, 525–532 (1985)). Globosides were produced with 18-carbon and 24-carbon fatty acids bearing a spin label at the C-16 position. Spin-labelled globosides were incorporated at 2 and 10 mol% into rigid, highly cooperative bilayer matrices of 1,2-dipalmitoylglycerophosphocholine (DPPC) and also into semi-fluid, non-cooperative membranes of DPPC/cholesterol. Recorded electron paramagnetic resonance (EPR) spectra were analysed by comparison with a library of standards representing samples of known composition. Spectra were manipulated using a computer program which permitted linear combination of standards to simulate coexistence of laterally separated domains of different composition. The most important conclusions ere as follows: (1) at least 80% of the globoside was definitely not confined to domains highly enriched in glycolipid, although there was evidence of binary-phase separation in the rigid DPPC/globoside matrix; (2) the presence of 33 mol% cholesterol reduced the evidence of globoside phase separation; (3) there was remarkably little difference in results whether the globoside fatty acid chain length was similar to that of the phospholipid host matrix or eight carbons longer. Temperature profiles derived over the phase-transition region of DPPC using spin-labelled globoside or an unattached amphiphilic spin label were consistent with these findings. The same systems lent themselves to consideration of the role of glycolipid fatty acid chain length and cholesterol in determining glycolipid crypticity in membranes: (1) polyclonal anti-globoside IgG bound to globoside in DPPC liposomes without inducing agglutination. (2) The same antibodies did agglutinate DPPC/cholesterol liposomes bearing globoside. (3) The effect of cholesterol probably was upon glycolipid dynamics or attitude in the membrane, rather than upon distribution. (4) These observations were basically unaffected by the choice of 18-carbon vs. 24-carbon glycolipid fatty acid. (5) It appears that the (tetrasaccharide) globoside sugar chain is sufficiently long that the importance of fatty acid chain length in determining headgroup ‘accessibility’ to antibodies is greatly reduced relative to the situation of monosaccharide species such as galactosylceramide.
Antibodies to phospholipids and liposomes: binding of antibodies to cells
1987, BBA - BiomembranesBinding of two monoclonal anti-liposome antibodies to the surface of cultured murine peritoneal macrophages was investigated by indirect immunofluorescence and enzyme-linked immunosorbent assay. Neither antibody bound to cultures of freshly explanted, nonadherent macrophages, but immunoreactivity was observed following cell adherence to tissue culture plastic. Fluorescent microscopic evaluation revealed heterogeneity in staining patterns of the antibodies on adherent cells. Binding both to viable and fixed adherent macrophages was observed even after a 10 000-fold dilution of antibody. Treatment of adherent macrophage cultures with trypsin increased antibody binding. Further treatment of trypsinized-macrophages with alkaline phosphatase or neuraminidase did not affect antibody binding, but phospholipase D and, to a greater extent, phospholipase C resulted in a marked decrease in cellular binding. The data indicate that antibodies produced against liposomes appear to bind to surface phospholipids of macrophages, but binding can be influenced by the physiological state of the macrophage and overlying cell surface proteins.
Glycosphingolipids and antitumor immunity
1987, BBA - Reviews on CancerSynthesis of ether glyceroglycolipids
1986, Chemistry and Physics of LipidsThe reaction of 1-O-aklyl-2-O-methylglycerols with acetobromosugars in the presence of mercury(II)cyanide leads to stereochemically uniform peracetylated 1-O-aklyl-2-O-methyl-3-O-β-D-glycosylglycerols after column chromatography. Alkaline hydrolysis of the latter compounds affords 1-O-alkyl-2-O-methyl-3-O-β-D-glycosylglycerols, i.e. ether glyceroglycolipids with potential antineoplastic activity. The sequence of reactions described is also applicable to the preparation of radioactively labeled ether glyceroglycolipids in high yields
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Present address: Department of Immunology, Kurume University, 67, Asahimachi Kurume, Fukuoka-830-91, Japan.