Stealth liposomes circulation time

Figure 8.4 Structure of unilamellar liposomes, (a) Liposomes are spherical lipid bilayers surrounding an aqueous core. Water-soluble drugs (triangles) can be entrapped in the core and lipid-soluble drugs can be dissolved in the bilayer, (b) Stealth liposomes are produced by adding lipids that are conjugated to a water-soluble polymer, most frequently PEG. (c) Liposomes can increase the circulation time of lipid-soluble drugs stealth liposomes circulate for longer periods than conventional liposomes.

Figure 1.1. Schematic representation of four major liposome types. Conventional liposomes are either neutral or negatively charged. Stealth liposomes are sterically stabilized and carry a polymer coating to obtain a prolonged circulation time in the body. Immunoliposomes are antibody targeted liposomes and can consist of either conventional or sterically stabilized liposomes. Positive charge on cationic liposomes can be created in various ways. Reproduced from reference [112] with permission.

Lipid moieties coupled to polyethylene glycol (PEG) have been used to increase the blood circulation time of lipoplexes (Fig. 32). The PEG-lipid conjugates such as DOPE-PEG, Chol-PEG, ceramides-PEG and their derivatives are then coformulated with the cationic lipid, helper lipid, and DNA. This results in coating the surface of the lipoplexes with PEG and preventing undesired association with plasma proteins or circulating cells (stealth liposomes). Recently, a-tocopheryl PEG-succinate (TPGS) was also used in gene delivery formulations because of its ability to confer not only a stealth property but also antioxidant and absorption enhancer properties [129]. 

Sterically stabilized ( stealth ) liposomes, which carry hydrophilic coatings, are used to obtain prolonged circulation times. 

DaunoXome liposomes are also long circulating liposomes, in this case encapsulating the cytostatic daunorubicin. Although a non-stealth system, long circulation times are attained by using a particularly rigid bilayer composition, in combination with a relatively small liposome size. 

In addition to PEGylation, polyvinyl pyrolidone (PVP) nanoparticles modified with hydrophilic polaxa-mine have been reported to adsorb less protein than the unmodified particles, conventional liposomes, and stealth liposomes.Polystyrene microspheres coated with lecithin and particles coated with Pluronic were also observed to adsorb less protein and demonstrate a prolonged blood circulation time without adversely affecting the safety profile of the drug. 

Sterically stabilized liposomal doxorubicin (pegylated liposomal doxorubicin Caelyx/Doxil) is coated with polyethylene glycol (3), which results in so-called stealth liposomes. In liposomal daunorubicin the liposome consists of a lipid bilayer of distearoylphosphati-dylcholine and cholesterol in a 2 1 molar ratio (4). Both formulations have a hydrophilic outer layer, which attracts a coating of water around the liposomal shell. This increases the circulation time by making the formulation virtually invisible to the reticuloendothelial system. 

Two pivotal discoveries enabled the full potential of liposomes to be realized. The first was the discovery in the late 1980s and early 1990s that the presence of additional molecules such as poly(oxyethylene) bonded onto the liposome surface deaeased their clearance by partially preventing liver and spleen uptake of i.v. injected liposomes. These are now often referred to as stealth liposomes as this effect enables them to escape recognition by the liver and spleen with the benefit of long circulation times. This observation was made almost in parallel with the discovery that polystyrene nanoparticles coated with a poly(oxyethylene) polymer also showed reduced fiver and spleen uptake. It is likely that a reduction in the coating of these liposomes by plasma proteins (opsonization), and their reduced aggregation in the blood are responsible for the increased circulation time of... 

Efficient liposomal therapeutics also require long circulation times. Normal liposomes are cleared from the blood rapidly by the reticuloendothehal systan, but circulation times can be easily increased by giving the liposomes a so-called stealth character. Stealth liposomes are sterically stabilized by lipids with a long polyethylene glycol unit attached to the headgroup, usually phosphatidylethanolamine (PE). ... 

More than thirty years have passed since Bangham described a liposome for the first time (14). Liposomes had been considered to be a carrier for the delivery of dmg because of non-toxic ceU-Uke stmcture. However the original liposomes possessed a drawback as the liposomes injected intravenously into animals were rapidly cleared primarily by the RES. Consequently they disappear before reaching the tumor tissues and exerting their ceU-kiUing effect. Thus requirements for liposomes with longer circulation times and improved avoidance of RES capture, became prerequisite, which was later accomplished by the development of stealth Uposome for cytotoxic dmg delivery (6-10). In the cases of stealth... 

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