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

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

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。

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 （FFX-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 distribu- ted in the micelles in an amorphous state. In pharmacokinetic studies, the AUC value of PTX-HA-PTX micellesincreased 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.