目的 将聚乙二醇1000维生素E琥珀酸酯（D-α-tocopherol polyethyleneglycol 1000 succinate，TPGS）接枝于壳聚糖（chitosan，CS）分子中，形成共聚物TPGS-CS，并以紫杉醇（paclitaxel，PTX）为模型药物，构建TPGS-CS/PTX载药胶束，考察其在大鼠各肠段吸收情况。方法 将琥珀酸酐（succinic anhydride，SA）、4-二甲氨基吡啶（4-dimethylaminopyridine，DMAP）与CS发生酰胺化反应，制备TPGS-CS共聚物，采用红外光谱仪和核磁共振波谱仪对产物进行表征。以PTX为模型药物，采用超声乳化法制备载药聚合物胶束，用HPLC法测定包封率和载药量；用动态光散射法（dynamic light scattering，DLS）测定粒径和Zeta电位；采用透射电子显微镜（transmission electron microscope，TEM）观察胶束形貌；基于在体肠吸收实验计算药物的吸收速度常数（absorption rate，K_a）。结果 红外与核磁结果表明，TPGS通过酰胺键接枝于CS上；TEM观察结果显示，胶束微观形态规整、粒径均匀；大鼠在体肠吸收实验证实，与PTX参比制剂相比，TPGS-CS/PTX胶束在大鼠各肠段吸收速率提高20%，提示该胶束载药系统可能具有更高的生物利用度。结论 成功构建了TPGS-CS胶束载药系统，胶束性质优良，与PTX参比制剂相比，一定程度提高了PTX的吸收速度常数，促进药物口服吸收。

Objective To obtain the intestines absorption of TPGS-CS/PTX polymeric micelles in rats, a drug-loaded micelle system was established by a kind of amphiphilic copolymer, D-α-tocopherol polyethylene glycol 1000 succinate-chitosan (TPGS-CS) was prepared by grafting D-α-tocopherol polyethyleneglycol 1000 succinate (TPGS) as the donor of the micelle hydrophobic group on chitosan (CS) as bioadhesive material, and loading paclitaxel as model drug. Methods TPGS was activated by its hydroxy-terminal carboxylation with succinic anhydride (SA) and 4-dimethylaminopyridine (DMAP). The TPGS-CS copolymer was prepared by the amidation of free amino groups on CS. The chemical structure of the TPGS-CS grafted copolymer was characterized by Fourier transform-infrared spectroscopy (FT-IR) and Nuclear magnetic resonance spectroscopy (NMR). The polymer micelle loading paclitaxel was selected as model drug and TPGS-CS/PTX was prepared by ultrasonic emulsification method. The encapsulation efficacy (EE) and drug loading (DL) were determined by high performance liquid chromatography (HPLC). The particle size, Zeta potential, and size distribution of the micelle system were measured by dynamic light scattering (DLS). The surface morphology of the micelles was investigated by Transmission electron microscopy (TEM). The in vivo intestines absorption rate (K_a) of paclitaxel-loaded TPGS-CS micelle was calculated in rats. Results The results of FT-IR and ¹H NMR indicated that the copolymer (TPGS-CS) was synthesized. The TEM result showed that the formed particles were uniform in shape without aggregation. The K_a of TPGS-CS/PTX was 20 percent higher in comparison to the reference preparation, it indicated that this polymeric micelles could increase bioavailability. Conclusion The proposed TPGS-CS copolymer was successfully synthesized in this experiment, and the drug-loaded micelles prepared by ultrasonic emulsification exhibited good characteristics compared with the reference preparation, the K_a of paclitaxel was increased to some extent to promote oral absorption of the drug.

国家自然科学基金资助项目（81573623）；国家自然科学基金资助项目（81760718）