Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, approve d by the FDA for the treatment of ovarian and breast cancers. Due to its lo w solubility in water, it is clinically administered dissolved in Cremophor EL, (polyethoxylated castor oil) and ethanol, which cause serious side eff ects. Inclusion of paclitaxel in liposomal formulations has proved to be a good approach to eliminating this vehicle and improving the drug's antitumo r efficacy. We prepared different conventional and PEGylated liposomes cont aining paclitaxel and determined encapsulation efficiency, physical stabili ty and drug leakage in human plasma. The best conventional liposome formula tion was composed of ePC/PG 9:1, while for PEGylated liposomes the best com position was ePC/PG/CHOL/PEG(5000)-DPPE 9:1:2:0.7. PEGylated liposomes were found to be less stable during storage than the corresponding conventional liposomes and to have lower drug release in human plasma at 37 degrees C. in vitro cytotoxic activities were evaluated on HT-29 human colon adenocarc inoma and MeWo melanoma cell Lines. After 2 and 48 h, conventional liposome s had the same cytotoxicity as free paclitaxel, while PEGylated liposomes w ere as active as free drug, only after 48 h. Pharmacokinetics and biodistri bution were evaluated in Balb/c mice after i.v. injection of paclitaxel, fo rmulated in Cremophor EL or in conventional or in PEGylated liposomes, Enca psulation of paclitaxel in conventional liposomes produced marked differenc es over the free drug pharmacokinetics. PEGylated liposomes were long-circu lating liposomes, with an increased t(1/2) beta 48.6 h, against t(1/2) beta 9.27 h of conventional liposomes. Biodistribution studies showed a conside rable decrease in drug uptake in MPS-containing organs (liver and spleen) a t 0.5 and 3 h after injection with PEGylated compared to conventional lipos omes. (C) 2000 Elsevier Science B.V. All rights reserved.