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Liposome Technical Information
@Long Circulation Liposome
In the late 1980s, polyethylene glycol (PEG) began to be used for modifying the surface of drugs such as proteins to reduce antigenicity or ensure drug stability in blood. This technology was focused and liposomes with surface modified by PEG derivatives were launched (Doxil® / Caelyx® 1995). The possible mechanisms for avoiding RES detection and prolonging retention in circulation are: 1) a hydrophilic layer is made on the surface of the liposome to inhibit adsorption of opsonin molecules such as complements and liposome uptake by the macrophage system is inhibited, and 2) uptake of liposome is inhibited because of a nonspecific decrease in adhesiveness of liposome itself to macrophages. The molecular weight of PEG used for PEG-liposomes used on the market is 2000, but stealth characteristics are effective when the molecular weight of PEG is between 1000 and 5000. PEG-conjugated phospholipids are used approximately 6 mol % in all the lipids consisting of the liposome, and the liposome diameter ranges from 100 - 200 nm.
Furthermore, polyglycerin (PG), an oligomer of glycerin, can also show prolonged retention in circulation when it is used as the aqueous high polymer instead of PEG. Other forms that have been shown to have the same effect include multi-arm PEG, and aqueous high polymer lipid derivatives with phospholipids conjugated with alkenyl ether-maleic anhydride copolymerization.
These stealth liposomes with their diameter adjusted at about 100 nm gather easily around tumor tissues because of the enhanced permeability retention (EPR) effect (proposed by Dr. Yasuhiro Matsumura and Dr. Hiroshi Maeda at Kumamoto University). Drug targeting to the tumor tissues is possible by incorporating anti-cancer drugs inside the liposome. The EPR effect means that high polymerized drugs and liposomes are selectively trapped by tumor tissues and stay there for a longer period of time because of the following characteristics of tumor tissues: (1) high neovascular density; (2) larger intracellular space (100 nm - 200 nm) in insufficient vessel structure; and (3) vascular hyperpermeability due to the vascular permeability factor.
As for commercial Doxil® / Caelyx®, Allen et al. recently studied and reported the effect of liposome diameter and the kind of fatty acids. Their report says the diameter below 157 nm is preferable and liposome with 255 nm diameter has slightly poorer tumor growth suppression. It is demonstrated that adjusting the diameter is the key to maximizing the EPR effect. Tumor suppression by the different phase transition temperatures is also studied. The lower the phase transition temperature replacing fatty acid in phosphatidylcholine (the main component) by oleic acid, the smaller the tumor suppression effect. The drug delivery effect to the tumor site had been low because the stability of liposome in circulation was impaired due to lower phase transition temperature.
Furthermore, polyglycerin (PG), an oligomer of glycerin, can also show prolonged retention in circulation when it is used as the aqueous high polymer instead of PEG. Other forms that have been shown to have the same effect include multi-arm PEG, and aqueous high polymer lipid derivatives with phospholipids conjugated with alkenyl ether-maleic anhydride copolymerization.
These stealth liposomes with their diameter adjusted at about 100 nm gather easily around tumor tissues because of the enhanced permeability retention (EPR) effect (proposed by Dr. Yasuhiro Matsumura and Dr. Hiroshi Maeda at Kumamoto University). Drug targeting to the tumor tissues is possible by incorporating anti-cancer drugs inside the liposome. The EPR effect means that high polymerized drugs and liposomes are selectively trapped by tumor tissues and stay there for a longer period of time because of the following characteristics of tumor tissues: (1) high neovascular density; (2) larger intracellular space (100 nm - 200 nm) in insufficient vessel structure; and (3) vascular hyperpermeability due to the vascular permeability factor.
As for commercial Doxil® / Caelyx®, Allen et al. recently studied and reported the effect of liposome diameter and the kind of fatty acids. Their report says the diameter below 157 nm is preferable and liposome with 255 nm diameter has slightly poorer tumor growth suppression. It is demonstrated that adjusting the diameter is the key to maximizing the EPR effect. Tumor suppression by the different phase transition temperatures is also studied. The lower the phase transition temperature replacing fatty acid in phosphatidylcholine (the main component) by oleic acid, the smaller the tumor suppression effect. The drug delivery effect to the tumor site had been low because the stability of liposome in circulation was impaired due to lower phase transition temperature.
   
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