Cholesterol in liposomes

Cholesterol autooxidation can occur. Not much information is available on autooxidation of cholesterol in liposomes (Lichtenberg and Barenholz, 1988). 

Schreier et al. [85] examined the effects of liposome encapsulation on the pharmacokinetics in sheep of amikacin, a water-soluble aminoglycoside. The dmg was formulated in 200 nm liposomes and administered by means of intratracheal instillation. The liposome formulations were soy PC/phosphatidyl glycerol (PG) (7 3 molar ratio) and soy PC/PG/CH (4 3 3). They found that both liposome formulations reduced plasma Cmax and prolonged the plasma half-life of the amikacin compared with the dmg administered as a solution, once again indicating that liposomes were controlling dmg delivery in the lungs. The inclusion of cholesterol in liposomes more than tripled the plasma half-life for the dmg compared with the liposomes without cholesterol. Cholesterol reduces the fluidity and permeability of liposomes in their liquid crystalline phase. 

Suwa, K., Kimura, T., and Schaap, A.P. (1978) Reaction of singlet oxygen with cholesterol in liposomal membranes. Effect of membrane fluidity on the photo-oxidation of cholesterol, Photochem. Photobiol., 28 469 473. 

Ohno-lwashita Y, Iwamoto M, Ando S, Iwashita S. Effect of lipidic factors on membrane cholesterol topology—mode of binding of theta-toxin to cholesterol in liposomes. Biochim Biophys Acta. 1992 1109(l) 81-90. 

Liposomes can be prepared from pure lipids or mixtures of lipids. Cholesterol is known to serve as a "fluidity buffer" it enhances the fluidity of the gel state bilayer, while it decreases the fluidity of the fluid state bilayer. Increasing concentrations of cholesterol in bilayers cause a broadening and gradual disappearance of the phase transition (Demel and De Kruyff, 1976). 

When liposomes are prepared from a molecular mixture of lipid components it is important that all lipids be homogeneously dissolved in an organic solvent in order to obteiin bilayers with evenly distributed lipids after hydration. For example, the solubilities of phosphatidylcholine and cholesterol in chloroform are similar their solubility in benzene differs. Upon removal of benzene from the lipid solution an inhomogeneous lipid film is formed on the glass wall and... 

Data about curcunfin encapsulated in liposomes have been reported recently. The authors encapsulated curcumin into a liposomal delivery system in order to study the in vitro and in vivo effects of this compound on proliferation, apoptosis, signaling, and angiogenesis using human pancreatic carcinoma cells. Carotenoids of different polarities and in competition with cholesterol were specifically incorporated into liposomes in order to mimic the physiological uptake by cells and monitor their antioxidant capacities. ... 

Probucol, another di-r-butyl phenol, is an anti-atherosclerotic agent that can suppress the oxidation of low-density lipoprotein (LDL) in addition to lowering cholesterol levels. The antioxidant activity of probucol was measured, using EPR, with oxidation of methyl linoleate that was encapsulated in liposomal membranes or dissolved in hexane. Probucol suppressed ffee-radical-mediated oxidation. Its antioxidant activity was 17-fold less than that of tocopherol. This difference was less in liposomes than in hexane solution. Probucol suppressed the oxidation of LDL as efficiently as tocopherol. This work implies that physical factors as well as chemical reactivity are important in determining overall lipid peroxidation inhibition activity (Gotoh et al., 1992). 

Effect of Cholesterol. Cholesterol inclusion into the lipid bilayers composed of DPPC or DSPC, eliminates apparent Tc and reduces permeability at and above the usual Tc. On the other hand, cholesterol inclusion increases packing of fluid bilayer composed of lipids with unsaturated fatty acyl chains. Since cholesterol rich liposomes are stable in plasma, cholesterol is commonly used as a liposomal component. 

The half-life of liposomes administered in the blood stream is affected by the composition, size, charge, and fluidity. Liposomes with a small size or with a rigid lipid bilayer have a longer half-life (38 9). Large liposomes administered iv tend to accumulate at a lymph node near the injected site. This tendency can be useful for preventing metastases. Liposomes which pass through the lymph node have a tendency to accumulate in the RES, such as the liver and spleen (40,41). The disposition of liposomes is altered by the dose of liposomes as well as size or lipid composition of liposomes. Cholesterol rich liposomes are cleared slower due to... 

Cholesterol s presence in liposome membranes has the effect of decreasing or even abolishing (at high cholesterol concentrations) the phase transition from the gel state to the fluid or liquid crystal state that occurs with increasing temperature. It also can modulate the permeability and fluidity of the associated membrane—increasing both parameters at temperatures below the phase transition point and decreasing both above the phase transition temperature. Most liposomal recipes include cholesterol as an integral component in membrane construction. 

Rudolf and Cliff [3.43] described the inclusion of hemoglobin in liposomes (LEH), to produce a stable blood substitute. The liposomes were formed from a solution of soya bean - phosphatidylcholine (soy PC), cholesterol, dimyristoyl-phosphatidyl, DL-glycerol (DMPG), and alpha-tocopherol with a ratio of 10 9 0.9 0.1. The product was dried and... 

One factor determining toxicity of AmB formulations is the form in which the antibiotic is released monomeric or aggregated because only self-associated AmB can complex cholesterol in eukaryote membranes (25). The differential toxicity of the lipid formulations toward macrophages could be related to their stability in the culture medium. For example, the Ampho-liposome formulation, which is destabilized in the presence of serum (24), has... 

Mayhew E, Rustum YM, Szoka F, et al. Role of cholesterol in enhancing the antitumor activity of cystosine arabinoside entrapped in liposomes. Cancer Treat Rep 1979 63 1923. 

Amphotericin-B is highly toxic as ergosterol is very similar to cholesterol and amphotericin has thus cross-reactivity to cholesterol in human cell membranes. Adverse effects include chills, fever, dyspnea, hepatotoxicity and anemia. However, nephrotoxicity is the most common complication, although adequate hydration can reduce the risk for this toxicity to some extend. Amphotericin induced nephrotoxicity may be irreversible. Liposomal preparations have shown to be therapeutically effective with little or no renal damage. 

MPEG-DSPE cholesterol— stealth liposomal pharmacology study, single- (transient effects in... 

Another significant component of many liposome preparations is cholesterol. In natural cell membranes, cholesterol makes up about 10—50% of the total lipid on a molar basis. For liposome preparation, it is typical to include a molar ratio of about 50% cholesterol in the total lipid recipe. The addition of cholesterol to phospholipid bilayers alters the properties of the resultant membrane in important ways. As it dissolves in the membrane, cholesterol orients itself with its polar hydroxyl group pointed toward the aqueous outer environment, approximately even, in a three-dimensional sense, with the glyceryl backbone of the bilayer s phosphodiglyceride components (Fig. 337). Structurally, cholesterol is a rigid component in membrane construction, not having the same freedom of movement that the fatty acid tails of... 

Prepare a liposome suspension, containing MPB—PE, at a total lipid concentration of 5 mg/ml in 0.05 M sodium phosphate, 0.15 M NaCl, pH 7.2. Activation of DPPE with SMPB is described in Section 2. A suggested lipid composition for vesicle formation is PC cholesterol PG MPB—PE mixed at a molar ratio of 8 10 1 1. The presence of relatively high levels of cholesterol in the liposomal recipe dramatically enhances the conjugation efficiency of the component MPB—PE groups (Martin et al., 1990). Any method of emulsification to create liposomes of the desired size and morphology may be used (Section 1). 

Liposomes were first proposed for drug topical administration to the skin more than 25 years ago by Mezei and Gulusekharam [1,2]. The basic components of liposomes are phospholipids (phosphatidylcholine, phophatidylethanolamine, phophatidylserine, dipalmitoyl phosphatidylcholine, and others), cholesterol, and water. Liposomes may vary significantly in terms of size (from tens of nm to microns) and structure. In liposomes, one or more concentric bilayers surround an aqueous core generating small or large unilamellar vesicles (SUV, LUV) or multilamellar vesicles (MLV), respectively [3]. 

More recently, Carafa et al. showed that niosomes could be obtained from polyoxyethylene sorbitan monolaurate-cholesterol in aqueous environment. These authors investigated the delivery of lidocaine HC1 and lidocaine base from vesicles through silicone membrane and nude mice skin [44]. It was found that only the charged molecule (loading pH 5.5) could be encapsulated within the vesicles ( 30%). This behavior was explained by the entrapment ability of the hydrophilic moiety within the aqueous core of the vesicles. The lipophilic unionized form of lidocaine (loading pH 8.6) remained unattached. The amount of lidocaine permeated through nude mice skin from these niosomes was similar to liposomes and only about twofold greater than from a micellar system. 

---