载紫杉醇的PEG修饰的大黄酸偶联物胶束的表征、体外释放及药动学研究

Characterization, in vitro release and pharmacokinetics of Paclitaxel-loaded PEGylated Carboxymethyl Chiosan-Rhein Conjugate Micelles

关键词:  聚合物胶束  大黄酸偶联物  紫杉醇  体外释放  药动学

Key words:  polymeric micelles  rhein conjugate  paclitaxel  in vitro release  pharmacokinetic

摘要:

目的 对载紫杉醇(paclitaxel,PTX)的聚乙二醇修饰的大黄酸偶联物[PEGylated carboxymethyl chiosan-rhein conjugate (polymeric),PTX/CRmP]胶束进行形态与结构表征,考察其体外(模拟血液环境中)释放情况及药动学特征。方法 通过透射电镜(transmission electron microscopy,TEM)、差示扫描量热法(differential scanning calorimetry,DSC)、X射线衍射(X-ray diffraction,XRD)对胶束的粒径、形态及结构等方面进行评价;在pH 7.4磷酸盐缓冲液(含0.8 mol·L^-1水杨酸钠)中进行PTX/CRmP胶束的体外释放研究,计算PTX的累积释放率,绘制累积释放曲线;以大鼠为模型,尾静脉注射PTX/CRmP胶束后,通过药-时曲线、药动学参数等对其进行药动学研究。结果 TEM显示PTX/CRmP胶束呈类球形,粒径约160 nm,分布均匀;DSC和XRD显示PTX几乎全部被CPmP胶束包载入其内核中。PTX/CRmP胶束在pH 7.4磷酸盐缓冲液(含0.8 mol·L^-1水杨酸钠)中24 h内累积释放率为92.2%,药物释放速率显著慢于Taxol^®。药动学研究表明,与Taxol^®组相比,PTX/CRmP胶束中药物的分布和消除较慢,药-时曲线下面积显著增加,CRmP胶束能延长PTX半衰期及其在血液循环系统中的循环时间。结论 CRmP偶联物物理包载PTX于内核中所得的PTX/CRmP胶束,粒径小,在体外模拟血液pH环境中缓释,PTX生物利用度提高。

Abstract:

OBJECTIVE To characterize the morphology and structure of PEGylated carboxymethyl chiosan-rhein conjugate(polymeric) micelles loaded with paclitaxel(PTX)(PTX/CRmP micelles), and to investigate the release in vitro and pharmacokinetic characteristics of PTX/CRmP micelles. METHODS Transmission electron microscopy(TEM), differential scanning calorimetry(DSC), X-ray diffraction(XRD) were used to evaluate the particle size, morphology and structure of micelles. The in vitro release of PTX/CRmP micelles was studied in pH 7.4 phosphate buffer solution(containing 0.8 mol·L^-1 sodium salicylate) to calculate the cumulative release rate of PTX and draw the cumulative release curve. The pharmacokinetics of PTX/CRmP micelles were studied by concentration-time curve and pharmacokinetic parameters after they were injected into the tail vein of rats. RESULTS TEM showed that PTX/CRmP micelles were spherical, with a particle size of about 160 nm and uniform distribution. DSC and XRD showed that PTX was almost all loaded into the core of CPmP micelles. The cumulative release of PTX/CRmP micelles in pH 7.4 PBS (containing 0.8 mol·L^-1 sodium salicylate) was 92.2% within 24 h, significantly slower than that of Taxol^®. In pharmacokinetic studies, drug distribution and elimination in PTX/CRmP micelles group were slower and AUC was enhanced. The CRmP micelles could prolong the half-life and circulation time of PTX in the blood circulation system. CONCLUSION PTX/CRmP micelles are obtained by physically encapsulating PTX in the cores of CRmP micelles, with a small particle size and slow PTX release in the simulated blood pH environment in vitro. The bioavailability of PTX is improved.