Characterization and cytotoxicity of novel polyethyleneglycol-modified liposome contained doxorubicin Free

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Polyethyleneglycol (PEG)-modified liposomes are able to avoid from catch by the reticuloendothelial system. It has been clarified that the prolongation of liposome circulation in the blood and passive targeting to the tumor was achieved by PEG modification of the liposomal membrane. In our previous study, we reported that the mixed PEG-modified liposomes by a mixture of PEG-DSG with short polyoxyethylene chains (Mw : 500) and that with long ones(Mw : 2000) were useful. The mixed PEG modification with different PEG-molecular weights increased the fixed aqueous layer thickness (FALT) around the liposome, compared to that of single PEG modification. Furthermore, we confirmed that mixed PEG modification of the doxorubicin (DOX)-containing liposomes improved the biodistribution and increased in the antitumor activity compared to that of the single PEG modifications, and are superior. However, in this mixed PEG modified liposome, PEG ratio of PEG500 and PEG2000 on liposomal membranes was considered to be changed gradually in blood and tumor. In this study, we synthesized novel PEG lipid with different double arm (Mw of PEGs : 500 and 2000)-PEG (DDA-PEG) and was clarified the characterization and cytotoxicity of this DDA-PEG modified liposome contained doxorubicin.

All liposome was prepared by Bangham method, using DSPC : cholesterol : DSPG : PEG (DDA-PEG or PEG 500- and PEG 2000-DSG ). The FALT around the liposomes was increased with the increase of the PEG-molecular weight. In mixed PEG-modified liposomes with long polyoxyethylene chain and short polyoxyethylene chain, the FALT increased more than that of single PEG-modified liposomes. It was considered that the mushroom structure of long polyoxyethylene chains was transformed into a brush structure because the short polyoxyethylene chains full into the gap of the long polyoxyethylene chains. On the other hand, the FALT of DDA-PEG-modified liposomes was shown same level, compared to maximum level of mixed PEG-modified liposomes. Namely, it was expected that a part of long polyoxyethylene chains was changed to brush structure by short polyoxyethylene chains in one molecule. As the PEG ratio of PEG500 and PEG2000 in DDA-PEG-modified liposome does not change, the efficacy of DDA-PEG-modified liposome was speculated to be maintaining in the body. The cytotoxicity on P388 leukemia cells by this DDA-PEG-modified liposome contained doxorubicin was shown to be higher than those of unmodified liposome and mixed PEG-modified liposome, suggested to be superior novel PEG modification. In conclusion, it was clarified that DDA-PEG lipid as novel PEG lipid on liposome modification has outstanding properties in the physical character and the cytotoxicity.