ABSTRACT
Polyethyleneglycol (PEG) has often been used for the modification of liposomes, but it is difficult to insert PEG on the surface of liposomes, and the effects of modification are not marked enough. In this study, we examined the fixed aqueous layer thickness (FALT) of single or mixed PEG (molecular weight, 340, 500, 900, 2000)-modified doxorubicin (DOX) liposomes, and physical character and biological properties of these liposomes. On single PEG-modification, as the PEG-molecular weight increased, FALT also increased, but the ratio of the increase was reduced. While on modification by a mixture of PEG2000 and PEG with a short polyoxyethylene chain (PEG340 or PEG500), FALT increased compared with the single PEG2000-modified value. Moreover, when liposomes were modified by mixture of PEG2000 and PEG500, we recognized the most suitable mixed rate (PEG2000, 500=2:1), showed the maximum FALT. On the other hand, in vivo, as increase of FALT, DOX concentrations increased in the plasma and in the tumor, decreased in the liver. Furthermore, liposomes with remarkable increase of FALT showed enhancement of antitumor activity. As a result, the connection among increase of FALT and improvement of circulation in blood, the involvement of antitumor activity of DOX of these liposomes was suggested.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacology , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Polyethylene Glycols/chemistry , Algorithms , Animals , Antibiotics, Antineoplastic/pharmacokinetics , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Cholesterol/chemistry , Doxorubicin/pharmacokinetics , Electrochemistry , Excipients , Lipids/chemistry , Liposomes , Male , Mice , Mice, Inbred Strains , Tissue DistributionABSTRACT
Many different methods of preparing liposomes exist, but the biological and physical properties of these preparations are not known. We therefore investigated the physical properties of liposomal doxorubicin (DOX) and found it to be most effective when administered intraperitoneally for carcinoma in the abdominal cavity. Liposomal DOX was prepared in three ways, by the Bangham method (BLDOX), pH gradient method, and gelation method. We investigated the physical properties of each preparation. And then we investigated the effects of the liposomes and liposomal lipids on the uptake of DOX by carcinoma cells in vitro and on the survival of Ehrlich ascites carcinoma-bearing mice in vivo. The uptake of DOX by the cells differed significantly with each liposome in vitro. The physical properties of the liposomes, including liposomal membrane lipids, size, zeta potentials and fluidity of liposomal membrane, were not so different, but the leak level of entrapped DOX from the liposomes was. Furthermore, the survival of ascites tumor-bearing mice also differed with each liposome preparation, DMPC containing BLDOX being the most effective when administered intraperitoneally. The method of preparation is an important factor affecting the properties of liposomes, and for local therapy, DMPC containing BLDOX is most effective because of its leaky property.
