Their History and Characteristics

Liposomes that are vesicles of lipid bilayers were first prepared in the 1960s. Liposome encapu-sulation has been proven useful for reducing the toxicity of drugs and increasing the solubility of hydrophobic drugs. However, liposomes tend to be trapped by the RES after intravenous injection. Therefore, allowing escape from the RES is one of the key strategies for developing cell-specific carriers because liposomes escaping from the RES accumulate in tumor tissue by a passive mechanism. As far as methods of escaping from the RES are concerned, Allen et al. in 198745 were the first to show that ganglioside and sphingomyelin (SM) synergistically acted to dramatically reduce the rate and extent of uptake of liposomes by the RES; therefore, this type of liposome is called a stealth liposome. In 1990, Klibanov et al.46 demonstrated that PEG-liposomes prepared as poly (ethylene glycol)-phosphatidylethanolamine conjugates (PEG-PE) could also reduce uptake by the RES. Because PEG is easy to prepare and relatively cheap, and it has controllable molecular weight and is able to bind to lipids or proteins, it can be used for active targeting such as glycosylated liposomes47 and immuno-liposomes.48

On the other hand, as far as active targeting is concerned, the receptor-mediated endocytosis systems present in various cell types would be useful, and a number of gene delivery systems were developed in the 1990s. Ligand-receptor recognition is an attractive tool for the development of cell-specific targeting systems; i.e., galactose to asialoglycoprotein receptors expressed on hepato-cytes parenchymal cell (PC),49 mannose to mannose receptors expressed on macrophages, sinusoidal endothelial cells, Kupffer cells, and dendritic cells,50 folate receptors expressed on cancer cells,51 and so on. As far as the size effect is concerned, it is possible to prepare liposomes of the size required by filtration. Because capillary vessels in a human tumor inoculated into SCID mice are permeable even to liposomes up to 400 nm in diameter,52 liposomes with a diameter less than 50-200 nm are typically used. On the other hand, with regard to the effect of the surface charge of liposomes, it is known that strongly cationic liposomes highly accumulate in the lung after intravenous injection. Table 4.1 summarizes liposomes for drug delivery.

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