基于透明质酸-紫杉醇前药的载药胶束的制备及大鼠体内药代动力学

以两亲性透明质酸-紫杉醇高分子前药(HA-PTX)为载体，制备包载PTX的高载药量纳米胶束；分别使用HPLC、动态光散射法(DLS)、透射电子显微镜(TEM)、原子力显微镜(AFM)和X线粉末衍射法(XRD)等手段对其载药量、包封率、粒径分布和胶束形态等进行测定或表征；采用荧光芘探针法测定HA-PTX的临界胶束浓度(CMC)；以市售紫杉醇注射剂(Taxol)为对照，通过大鼠体内药代动力学实验考察载药胶束的体内过程。载药胶束PTX-HA-PTX化学偶联药物和物理包载药物总量高达41.8%，包封率高达95.4%，平均粒径为213.2 nm，Zeta电位为-15.5 mV；XRD结果确证药物以分子状态或无定型状态存在于胶束内部；TEM和AFM显示胶束呈类球形；大鼠药代动力学结果显示，相对于Taxol，PTX-HA-PTX胶束组的血药浓度时间曲线下面积(AUC)显著提高(P<；0.01)，而清除率(CL)显著下降(P<；0.05)，说明PTX-HA-PTX胶束可延缓PTX在体内的消除，延长滞留时间，提高药效。结果表明HA-PTX可作为优良的增溶载体，具有良好的应用前景。

Drug-loaded micelles based on hyaluronic acid-paclitaxel prodrug: preparation and pharmacokinetic study in rats

The aims of this study were to prepare high paclitaxel loading amount polymeric micelles based on amphiphilic hyaluronic acid-paclitaxel prodrug. The drug-loading and entrapment efficiency were characterized by HPLC. The physico-chemical properties of PTX loaded HA-PTX micelles(PTX-HA-PTX)was characterized by dynamic light scattering(DLS), transmission electron microscope(TEM), atomic force microscopy(AFM)and X-ray diffraction(XRD), respectively. The critical micelle concentration(CMC)was determined by fluorescence pyrene probe techniques. The pharmacokinetics behaviors of PTX-HA-PTX micelles were performed in rats taking Taxol as control. It was found that the drug-loading and encapsulation efficiency of PTX-HA-PTX micelles reached up to 41. 8% and 95. 4%, respectively. The nanoparticle size was approximately 213. 2 nm and the Zeta potential was -15. 5 mV. PTX-HA-PTX micelles exhibited to be almost spherical in shape from the observation by TEM and AFM. XRD results confirmed that PTX was either molecularly dispersed in the polymers or distributed in the micelles in an amorphous state. In pharmacokinetic studies, the AUC value of PTX-HA-PTX micelles increased significantly(P< 0. 01)while the CL value decreased significantly(P< 0. 05)compared with Taxol, which indicated slower clearance rate, prolonged residence time and enhanced therapeutic effect. All the results demonstrated that PTX-HA-PTX micelles might be a promising PTX delivery carrier for efficient tumor therapy.