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At least 19 recordsLinked to original sources
PubMed1992

Liposomal modification with uronate, which endows liposomes with long circulation in vivo, reduces the uptake of liposomes by J774 cells in vitro.

For overcoming rapid removal of liposomes from the bloodstream, we developed reticuloendothelial system (RES)-avoiding liposomes modified with a uronic acid derivative, palmityl-D-glucuronide (PGlcUA). In this current study, we examined the in vitro interaction of PGlcUA-liposomes with J774 cells derived from mouse macrophages. Liposomal association with J774 cells at 37 degrees C did not increase compared with the binding at 4 degrees C when liposomes were modified with PGlcUA. RES-avoiding ability was not specifically endowed by glucuronate but by uronates in general, since palmityl-D-galacturonide showed a similar effect on liposomal clearance in vivo and liposomal uptake in vitro. These facts indicate that modification of the liposomal surface with uronic acid derivatives endows liposomes with a long circulation time in the bloodstream by reducing their uptake by macrophages.

Animals↗
PubMed1992

Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes.

We have examined the effect of liposome size on liposome circulation time in the blood. Liposomes composed of phosphatidylcholine, cholesterol and ganglioside GM1 were prepared in the various size range. Optimal circulation activity (55% injected dose at 4 h post injection) of GM1-containing liposomes, which correlated with a relatively high uptake of liposomes by EMT6 tumor in mouse, was obtained with a size range of 70 to 200 nm in diameter. Increasing the diameter of liposome to greater than 200 nm resulted in an enhancement of the spleen uptake and decrease of the blood level. For liposomes with a diameter of less than 70 nm, 70% of the injected dose were taken up by the liver, presumably by the parenchymal cells. In contrast, the biodistribution of phosphatidylserine-containing liposomes was relatively insensitive to changes in liposome size; most of the injected dose was found in the liver. The effect of RES blockade on the circulation time of large (d greater than 300 nm), GM1-containing liposomes was also studied. Dextran sulfate 500, a commonly used blockade reagent for Kupffer cells, had no effect. On the other hand, preinjection of a large dose of liposomes with a diameter greater than 500 nm showed variable results depending on the lipid composition of the blocking liposomes. Preinjection of liposomes containing GM1, phosphatidylinositol or (N-polyethyleneglycol) phosphatidylethanolamine effectively reduced the spleen uptake of the large GM1-containing liposomes, whereas liposomes containing phosphatidic acid showed no effect. These results indicate that only spleen homing liposomes can be used as a blocking reagent to prolong the circulation time of the large GM1-containing liposomes.

Animals↗
PubMed1992

Delivery of plasmid DNA into mammalian cell lines using pH-sensitive liposomes: comparison with cationic liposomes.

We compare the transfection efficiency of plasmid DNA encoding either luciferase or beta-galactosidase encapsulated in pH-sensitive liposomes or non-pH-sensitive liposomes or DNA complexed with cationic liposomes composed of dioleoyloxypropyl-trimethylammonium:dioleoylphosphatidyl-eth anolamine (1:1, w/w) (Lipofectin) and delivered into various mammalian cell lines. Cationic liposomes mediate the highest transient transfection level in all cell-lines examined. pH-sensitive liposomes, composed of cholestryl hemisuccinate and dioleoylphosphatidylethanolamine at a 2:1 molar ratio, mediate gene transfer with efficiencies that are 1 to 30% of that obtained with cationic liposomes, while non-pH-sensitive liposome compositions do not induce any detectable transfection. Cationic liposomes mediate a more rapid uptake of plasmid DNA, to about an eightfold greater level than that obtained with pH-sensitive liposomes. The higher uptake of DNA mediated by Lipofectin accounts for part of its high transfection efficiency. Treatment of cells with chloroquine, ammonium chloride, or monensin decreases (threefold) transfection using pH-sensitive liposomes and either has no effect on or enhances cationic liposome-mediated transfection. Therefore plasma membrane fusion is not the only mechanism available to cationic liposomes; in certain cell lines DNA delivery via endocytosis is a possible parallel pathway and could augment the superior transfection efficiency observed with cationic liposomes.

Cell Line↗
PubMedDate not supplied

Liposomes as carriers of macrolides: preferential association of erythromycin A and azithromycin with liposomes of phosphatidylglycerol containing unsaturated fatty acid(s).

To assess the most favourable phospholipid composition of a liposomal carrier for antibiotics, small multilamellar liposomes were prepared from phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol of varying fatty acid composition in the presence of erythromycin A and azithromycin. Crude liposomes were subjected to Sepharose CL-4B column chromatography, and liposomes containing antibiotics were well separated from free antibiotics. These experiments established that the greatest association of antibiotics was achieved with liposomes prepared from phosphatidylglycerol rather than phosphatidylcholine or phosphatidylethanolamine. Furthermore, the composition of fatty acids in phosphatidylglycerol liposomes influenced the amount of antibiotics associated with liposomes; the highest amount was obtained with dioleoylphosphatidylglycerol followed by phosphatidylglycerol of fatty acid composition similar to that of egg yolk lecithin. It was established that purified liposomes, prepared from [3H]phosphatidylglycerol containing unsaturated fatty acid(s) bind about 25 per cent of originally present antibiotic. Both antibiotics, erythromycin A and azithromycin, were similar in respect to the amount of their association with liposomes. Determination of the size of phosphatidylglycerol/antibiotic liposomes established that the mean diameter of liposomes containing antibiotics was 200-350 nm, very close to that of liposomes without them.

Anti-Bacterial Agents↗
PubMed1992

Adjuvant effects of liposomes containing lipid A: enhancement of liposomal antigen presentation and recruitment of macrophages.

Liposomes containing lipid A induced potent humoral immune responses in mice against an encapsulated malaria antigen (R32NS1) containing NANP epitopes. The immune response was not enhanced by lipid A alone or by empty liposomes containing lipid A. Experiments to investigate the adjuvant mechanisms of liposomes and lipid A revealed that liposome-encapsulated R32NS1 was actively presented by bone marrow-derived macrophages to NANP-specific cloned T cells. The degree of presentation was related to the amount of liposomal antigen added per macrophage in the culture medium. At high cell densities, poor presentation occurred when liposomes lacked lipid A but excellent presentation occurred when the liposomes contained lipid A. Liposomes containing lipid A and encapsulated antigen also activated gamma interferon-treated macrophages to produce nitric oxide. Macrophage activation and antigen presentation occurred with liposomes that could not be detected by the Limulus amebocyte lysis assay. Intraperitoneal injection of liposomal lipid A caused a marked increase in the recruitment of immature (peroxidase-positive) macrophages to the peritoneum. On the basis of these experiments, we propose that the mechanism of the adjuvant action of liposomal lipid A is partly due to increased antigen presentation by macrophages and partly due to recruitment of an increased number of macrophages serving as antigen-presenting cells.

Adjuvants, Immunologic↗
PubMed1992

Fusion of influenza virus particles with liposomes: requirement for cholesterol and virus receptors to allow fusion with and lysis of neutral but not of negatively charged liposomes.

Influenza virus particles are able to fuse with liposomes composed of negatively charged or neutral phospholipids, as shown by using fluorochrome-labelled virions and fluorescence dequenching methods. Fusion with liposomes composed of only phosphatidylcholine (PC) was dependent on the presence of cholesterol (Chol), whereas fusion with liposomes containing negatively charged phospholipids, such as phosphatidylserine (PS), or of PC and phosphatidylethanolamine (PE) occurred in the absence of Chol. Fusion of influenza virions with PC:Chol liposomes was observed at pH 5.0, but not at pH 7.4, whereas a low degree of fusion with negatively charged liposomes or those containing PE was observed at pH 7.4. In addition, non-fusogenic influenza virions or HA0 influenza virions fused with PS- or PE-containing liposomes, especially at pH 5.0. Influenza virus particles were also able to induce the release of the fluorochrome calcein from negatively charged calcein-loaded liposomes at pH 5.0, as well as at pH 7.4, but failed to do so with PC:Chol liposomes. Lysis of PC:Chol by influenza virions was dependent on the presence of virus receptors, namely gangliosides (sialoglycolipids), and was observed only at pH 5.0. The results show that fusion of influenza virions with negatively charged or PE-containing liposomes does not reflect the biological activity of the virus needed for penetration and infection of living cells. On the other hand, fusion with PC:Chol liposomes is probably due to the activity of the viral fusion protein, the haemagglutinin glycoprotein.

Cholesterol↗
PubMed1991

Comparison of dynamics of lecithin liposomes and brain total lipid liposomes with synaptosomal membranes. An EPR spectroscopy study.

Dynamics and/or order of the hydrophobic part of phosphatidylcholine (PC) liposomes and rat brain total lipid (TL) liposomes and synaptosomes were studied and compared by EPR spectroscopy using the spin probes 5 or 16-doxyl stearic acid and 14-doxyl phosphatidylcholine. The dynamics and/or order of the hydrophobic part of TL liposomes or synaptosomes were similar but differed largely from those of PC liposomes. The dynamics of the hydrophobic part of the liposomes decreased gradually with the increasing TL/PC ratio in the sample. To obtain in TL liposomes or synaptosomes the same EPR spectrum parameters as in PC liposomes at 37 degrees C, the formers have to be heated to temperatures of approximately 50-60 degrees C. The dynamics and/or order of the hydrophobic part of lecithin liposomes at 5-10 degrees C were comparable with those of TL liposomes or synaptosomes at 37 degrees C. The results emphasize the role of the lipid composition in studies concerning drug-lipid and protein-lipid interactions in model and biological membranes.

Animals↗
PubMed1990

Effect of liposome composition and other factors on the targeting of liposomes to experimental tumors: biodistribution and imaging studies.

We have examined the distribution of radiolabeled liposomes in tumor-bearing mice after i.v. injection. Two mouse tumors (B16 melanoma, J6456 lymphoma) and a human tumor (LS174T colon carcinoma) inoculated i.m., s.c., or in the hind footpad were used in these studies. When various liposome compositions with a mean vesicle diameter of approximately 100 nm were compared using a radiolabel of gallium-67-deferoxamine, optimal tumor localization was obtained with liposomes containing a phosphatidylcholine of high phase-transition temperature and a small molar fraction of monosialoganglioside or hydrogenated phosphatidylinositol (HPI). At 24 h after injection, average values of tumor uptake higher than 10% of the injected dose per g and liver-to-tumor ratios close to 1 were reproducibly obtained. Increasing the molar fraction of HPI from 9% to 41% of the total phospholipid resulted in enhancement of liver uptake and decrease of tumor uptake. Methodological aspects that influence vesicle size appear to affect significantly liposome localization in the tumor. However, varying the phospholipid dose within a 10-fold range caused only minor changes in the percent of injected dose recovered in the tumor. A high uptake by tumors was also observed using other radiolabels [[3H]inulin and indium-111-labeled bleomycin (111In-Bleo)] in monosialoganglioside- and HPI-containing liposomes. In the case of 111In-Bleo, encapsulation in liposomes resulted in approximately 20- to 40-fold increase in tumor accumulation of the radiolabel at 24 h after injection. The marked localization of liposomes in the mouse footpad inoculated with tumor as opposed to the contralateral mock-injected footpad was also documented by imaging experiments with gallium-67-deferoxamine and 111In-Bleo-labeled liposomes. These results support the contention that some glycolipid-containing liposomes previously shown to have long circulating half-lives accumulate significantly in a variety of tumors and are promising tools for the delivery of anti-tumor agents.

Animals↗
PubMed1991

Separation of large unilamellar liposomes from blood components by a spin column procedure: towards identifying plasma proteins which mediate liposome clearance in vivo.

In order to facilitate the isolation of liposomes from blood components, we have developed a simple and rapid procedure combining chromatographic and centrifugal methods. This 'spin column' procedure was used to isolate liposomes from incubation mixtures with human serum or from the blood of CD1 mice after intravenous administration of liposomes. An advantage of this procedure is that processing times are fast (typically minutes) such that the isolation procedure can be done in the absence of chelators or other coagulation inhibitors which may affect protein/liposome interactions. Furthermore, several samples can be analyzed together and small sample volumes can be processed. In addition, we show that this spin column procedure can be employed to isolate large unilamellar vesicles averaging 100 nm in diameter from lipoproteins and plasma proteins. The applicability of this spin column procedure in studying protein/liposome interactions is demonstrated by quantitating the amount of human complement component C3 bound per liposome using a C3 competitive ELISA assay after incubation with human serum. The proteins associated with the recovered liposomes were further analyzed by conventional SDS-polyacrylamide gel electrophoresis. We show that egg phosphatidylcholine/cholesterol (55:45, mol/mol) or egg phosphatidylcholine/cholesterol/dioleoylphosphatidylserine (35:45:20, mol/mol) liposomes isolated from the circulation of CD1 mice within minutes of administration have distinct, complex profiles of associated proteins. By isolating circulating large unilamellar liposomes using the spin column method and characterizing the proteins associated with their membranes, this protein fingerprinting approach will expedite identifying protein interactions which affect liposome stability and clearance in vivo.

Animals↗
PubMed1992

In vitro cytotoxicity of liposome-encapsulated doxorubicin: dependence on liposome composition and drug release.

We have investigated the in vitro cytotoxicity of free doxorubicin (DOX) and liposome-entrapped DOX (L-DOX) against a human ovarian carcinoma cell line (OV-1063) using a colorimetric assay. DOX was encapsulated in the inner water phase of liposomes by an ammonium sulfate-generated proton gradient. Liposomes varied in phospholipid composition but were of a similar size. It was found that the cytotoxic activity of L-DOX is substantially decreased when liposomes containing phospholipids of high phase-transition temperature (Tm) are used. The type of negatively charged headgroup did not have any significant influence on the cytotoxicity observed. Experiments using resin beads that bind free and protein-bound DOX, but do not interact with L-DOX, indicated that the cytotoxic effect is mediated by the release of drug from the liposomes into the extracellular medium; no evidence was found for direct cellular uptake of liposome-encapsulated drug. The use of the ionophore nigericin to induce the release of DOX from high-Tm liposomes increased cytotoxicity to a level comparable to free DOX, suggesting that 'remote release' techniques may substantially improve the efficiency of liposome-mediated drug delivery and allow for the full exploitation of the favorable pharmacokinetic properties of specific high-Tm formulations.

Cell Division↗
PubMed1991

Comparison of perturbation effect of propranolol, verapamil, chlorpromazine and carbisocaine on lecithin liposomes and brain total lipid liposomes. An EPR spectroscopy study.

Effect of verapamil, propranolol, chlorpromazine and carbisocaine on dynamics and/or order of liposomes (perturbation effect), prepared from different molar ratios of lecithin (PC) and rat brain total lipids (TL) was studied by EPR spectroscopy using spin probes 16-doxyl stearic acid and 14-doxyl phosphatidylcholine. The PC liposomes had higher dynamics and/or lower order than the TL liposomes. The perturbation effect of the drugs depended largely on the lipid composition of the liposomes. The drugs at the drug/lipid molar ratios from 0.1 to 1 increased membrane dynamics and/or decreased membrane order. The drugs had the most pronounced perturbation effect in the liposomes prepared from brain total lipids. The effect of the drugs decreased with decreasing the TL/PC ratio in the liposomes and was lowest, almost diminished, in the PC liposomes. Increasing concentration of the drugs decreased the difference between the dynamics and/or order of the PC and TL liposomes and so eliminated the influence of lipid composition on these membrane parameters. The results emphasize the role of lipid composition in studies concerning drug-lipid interactions in model and biological membranes.

Animals↗
PubMedDate not supplied

Liposomes as cyclosporin A carriers: ESR study of cyclosporin A interaction with 1,2-dimyristoyl-sn-3-phosphatidylglycerol liposomes.

In order to study the interaction of cyclosporin A (CsA) with phosphatidylglycerol liposomes, thermally induced changes of 1,2-dimyristoyl-sn-3-phosphatidylglycerol (DMPG) liposomes and DMPG liposomes containing CsA were studied by electron spin resonance (ESR) spectroscopy using 5-, 7-, 10-, 12- or 16-nitroxide stearic acid (NO-SA) as spin probes. All liposomes were purified by Sepharose 4B column chromatography and the molar ratio of [14C]DMPG/[3H]CsA in these liposomes was found to be 31.1 +/- 0.6. ESR spectroscopy established that the gel-to-liquid crystalline phase transition of DMPG liposomes occurred sharply at 22 degrees C, shifted significantly to 26-34 degrees C in the presence of CsA, detected with 5-, 7-, 10- and 12-NO-SA probes. Furthermore, transitions at 23 degrees C and 31 degrees C were detected with 16-NO-SA probe in the same liposomes containing CsA. It was concluded that CsA interacts with both the polar head group region and the entire hydrocarbon region of DMPG and must be embedded in the hydrophobic region of liposomes.

Cyclosporine↗
PubMed1976

Evaluation of liposome-entrapped radioactive tracers as scanning agents. Part 1: Organ distribution of liposome (99mTc-DTPA) in mice.

We describe the use of liposomes as a delivery system for radiopharmaceutical localization. Liposomes [99mTc-DTPA] were injected intravenously in mice and showed preferential uptake in the liver and spleen. There was a steady decline of activity in all organs, suggestive of destruction of liposomes with subsequent release of 99mTc-DTPA into the circulation. Alteration of uptake from liver to spleen, lung, and bone marrow was achieved by prior loading of the circulation with nonradioactive liposomes. The same effect was produced in dogs and demonstrated with scintigraphy. We also showed scintigraphically in dogs how 99mTc-DTPA, when administered entrapped in liposomes, follows the pattern of distribution of liposomes. Liposomes seem to be suitable carriers for radiopharmaceuticals. Further studies should show the possibility of directing liposomes to specific targets.

Animals↗
PubMed1976

Lectin-receptor interactions in liposomes. II. Interaction of wheat germ agglutinin with phosphatidylcholine liposomes containing incorporated monosialoganglioside.

Bovine brain gangliosides incorporated into phospholipid liposomes provide receptors for wheat germ agglutinin. Purified monosialogangliosides were mixed with egg phosphatidylcholine, and unilamellar liposomes were generated. Addition of wheat germ agglutinin induced the liposomes to fuse, and gel filtration analysis revealed that the lectin was incorporated into the fused liposomes. The fusion process was studied by following the changes in the 90 degrees light scattering. Increasing the proportion of the monosialoganglioside in the liposomes was found to increase both the extent of the lectin-induced liposome fusion and the rate of the reaction; below a threshold of approx. 5 mol%, the process was extremely slow. The increase in light scattering could be prevented by the addition of the hapten inhibitor, N-acetyl-D-glucosamine (1 mM). Addition of the inhibitor, subsequent to the lectin, caused a partial decrease in light scattering due to the dissociation of unfused vesicle aggregates. Electron microscopic examination revealed that the ganglioside-containing liposomes were vesicles, 244 +/- 25 A (S.D.) in diameter. Upon addition of wheat germ agglutinin, the vesicles appeared to fuse to form larger vesicles, corresponding to dimers and trimers of the initial vesicles. Inhibition studies with a variety of monosaccharides indicated that the sialic acid moieties present in the ganglioside acted as the lectin-receptor sites. This was confirmed by the observation that wheat germ agglutinin did not interact with phosphatidylcholine vesicles containing desialyated ganglioside.

Binding Sites↗
PubMed1991

Surface modification of haemoglobin-containing liposomes with polyethylene glycol prevents liposome aggregation in blood plasma.

With a view to prevention of liposome aggregation in plasma which is a lethal problem when using artificial erythrocytes, modification of the liposome surface with polyethylene glycol (PEG)-bound cholesterol or phospholipid was studied. The cholesterol or phospholipid moiety works as a scaffold for immobilization of the modifiers to the liposome. The modified liposome aggregability is significantly reduced with increased PEG content and particularly with increased PEG chain length. In addition, the zeta potential of modified liposomes decreases with increased PEG chain length. It is concluded that the long PEG chain exposed on the liposome surface prevents the adsorption of plasma proteins on to the surface by its excluded volume effect and, as a result, effectively reduces the liposome aggregability in plasma.

Erythrocyte Aggregation↗
PubMed1992

The intestinal and serum humoral immune response of mice to systemically and orally administered antigens in liposomes: I. The response to liposome-entrapped soluble proteins.

The development of oral vaccines is of great importance in veterinary medicine and new adjuvants and carriers are essential to this aim. Liposomes are effective systemic adjuvants but the relatively little data on their potential as oral adjuvants is inconclusive. Liposomes containing ovalbumin (OA) were effective adjuvants when administered intraperitoneally to mice. Feeding mice with OA or keyhole limpet haemocyanin in liposomes in a series of priming and boosting regimes failed to elicit any significant increase in serum or intestinal antibody response compared with feeding the free antigen. Oral tolerance induction to systemic challenge was also unaffected by OA entrapment in liposomes. In vitro liposome stability assays at 37 degrees C demonstrated a substantial resistance to disruption in the presence of acidic stomach contents. However, the addition of bile caused a rapid and profound release of protein marker from the liposomes. The rate and degree of disruption was influenced by the type of phospholipid used. These results suggest that liposomes may be useful as carriers for orally administered compounds but they are ineffective as adjuvants for the non-particulate, naturally weak immunogens used in this study.

Adjuvants, Immunologic↗
PubMed1979

Naturally occurring antibodies to liposomes. I. Rabbit antibodies to sphingomyelin-containing liposomes before and after immunization with unrelated antigens.

Liposomes were prepared from a mixture of sphingomyelin, cholesterol, and dicetylphosphate or L-alpha-dimyristoyl phosphatidylcholine, cholesterol, and dicetylphosphate, in the presence of glucose. The amount of trapped glucose released from these liposomes was monitored after incubation with a variety of normal and immune sera in the presence of guinea pig complement. All normal rabbit sera tested were found to release, in the presence of complement, detectable amounts of trapped glucose from sphingomyelin-containing liposomes. After immunization with a variety of unrelated antigens, the anti-sphingomyelin liposome activity increased signficantly and in direct proportion to the number of injections, despite the fact that the liposomes used in the assay did not contain the relevant antigen used for immunization. Liposomes prepared from dimyristoyl phosphatidylcholine showed only marginal release of their trapped marker when assayed with the same rabbit sera and complement. These liposomes, however, were fully reactive when the appropriate antigen was inserted in their bilayer structure. The antiliposome activity was associated mainly with the IgM antibody class. These results raise the interesting possibility that antigenic stimulation may trigger the activation of lymphocyte clones directed against autologous cell-membrane components that cross-react with artificial model membranes containing sphingomyelin.

Animals↗