PCL修饰的Pluronic共聚物胶束克服肿瘤多药耐药性的研究

摘要

Although the current clinical formulation of paclitaxel (Taxol) has a promising clinical activity against a wide variety of tumors, it shows significant side effects associated with its formulation in a 1:1 (v/v) mixture of Cremophor EL and dehydrated alcohol. In order to avoid these problems, a novel polymeric micellar formulation of paclitaxel (PTX) with Pluronic/poly (caprolactone) was prepared. The preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of paclitaxel-containing biodegradable polymeric micellar system (P105/PCL50/PTX) in comparison with Taxol were investigated. Copolymeric micelles were prepared by dialysis method using a ontoxicsurfa ctant Pluronic P105 modified with a low molecular weight poly (caprolactone), and paclitaxel. Using a dynamic light scattering sizer and a transmission electron microscopy, it was shown that the PTX-loaded copolymeric micelles had a mean size of approximately 150 nm with narrow size distribution and a spherical shape. In vitro release profiles indicated that the release of paclitaxel from these micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic assessment in rats, in which t1/2β and AUC of the micelle formulation were 4.0 and 2.2-fold higher than that of Taxol injection. And biodistribution study in mice showed that the PTX-loaded P105/PCL50 micelles not only decreased drug uptake by liver, but also prolonged drug retention in the blood, and increased the distribution of drug in kidney, spleen, ovaries and uterus. These results suggested that the polymeric micelles may efficiently load, protect and retain PTX in in vitro and in vivo environment, and could be useful drug carrier for intravenous administration of PTX.