Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing water-soluble prodrugs of paclitaxel

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, used cl inically for the treatment of ovarian and breast cancer. Due to its aqueous insolubility it is administered dissolved in ethanol and Cremophor EL (pol yethoxylated castor oil), which has serious side effects. In order to elimi nate this vehicle, in previous work we entrapped paclitaxel in conventional and in polyethylene glycol coated liposomes. However, in neither formulati on did we obtain satisfactory entrapment efficiency. In this study we incre ased the paclitaxel concentration entrapped in liposomes by incorporating d ifferent water-soluble prodrugs, such as the 2'-succinyl, 2'-methylpyridini um acetate and 2'-mPEG ester paclitaxel derivatives, in the lipid vesicles. Liposomes containing 2'-mPEG (5000)-paclitaxel showed the best performance in terms of stability, entrapment efficiency and drug concentration (6.5 m g ml(-1)). The in vitro cytotoxic activity of this liposomal prodrug was si milar to that of the parent drug. The pharmacokinetic parameters for the fr et: and for the liposomal prodrugs fitted a bi-exponential plasma dispositi on. The most important change in pharmacokinetic values of the prodrug vs. the free drug liposomal formulations was t(1/2)beta, plasma lifetime, which was longer in liposomes containing 2'-mPEG (5000)-paclitaxel. (C) 2000 Els evier Science B.V. All rights reserved.