Liposomal Anti-Cancer Drug Researches-The Myth of Long Circulation
摘要
The second generation liposomal anticancer drug is characterized by long-circulating half-life, which leads to passive tumor targeting and improved antitumor activity. Its development is based mainly on the surface coating of polymers and thus reducing its clearance from reticuloendothelial system. Is it possible to further improve the activity of liposomal drug through prolonging circulation time? We developed a liposomal system composed of distearoyl phosphatidylcholine (DSPC) and cholesterol with surface coating with polyethylene glycol (PEG). This liposome has a longer circulation half-life in animal and human than Doxil. Unfortunately, we found that with PEGylation, the tumor accumulation efficiency of this liposomal doxorubicin was reduced although the plasma concentration-time curve (AUC) was increased. The activity of this PEGylated liposomal doxorubicin (PLD), Lipo-Dox, is not higher than free doxorubicin in clinical studies. The most annoying toxicity of PLD, stomatitis, appeared at 30 mg/m^2 and became dose limiting at 50 mg/m^2, much lower than that of Doxil, 80mg/m^2. Present indications of PLD including salvage therapy of ovarian cancer, treatment of cancer patients with liver dysfunction and substitute of doxorubicin to avoid the toxicities of free drug. To increase PLD activity, enhancement of intracellular delivery through ligand-directed targeting system is the main focus of present liposomal anticancer drug development.