目的 新型树状大分子（PAMAM-co-0.25OEG，PGD）作稳定剂制备多烯紫杉醇（Docetaxel，DTX）纳米粒，以提高多烯紫杉醇的溶解度和生物利用度。方法 将多烯紫杉醇（DTX）、PGD按药载比8：1，采用超声沉淀联合高压均质法制备DTX-PGD纳米粒，动态光散射测定载药纳米粒粒径及电位；考察37℃条件下，DTX-PGD纳米粒在生理盐水、5%葡萄糖、PBS及血浆中的稳定性及DTX-PGD纳米粒的溶血性。X射线粉末衍射法测定DTX在纳米粒中的晶型形式。透析法测定DTX-PGD纳米粒的体外释放度，MTT法检测DTX-PGD纳米粒对4T1细胞的杀伤作用。结果 多烯紫杉醇在水中的溶解度提高到1.6 mg/mL（原药在水中几乎不溶），纳米粒载药量达65.7%。DTX-PGD纳米粒粒径270.7 nm，PDI值为0.112，电位28.6 mV。DTX-PGD纳米粒在5%葡萄糖及血浆中稳定存在。扫描电镜观察纳米粒为片状，XRD图谱显示，多烯紫杉醇在纳米粒中以晶体形式存在。DTX-PGD纳米粒在PBS缓冲液中释放缓慢，有较好的缓释效果。溶血实验得知，DTX-PGD纳米粒无溶血现象，可采用静脉注射法给药。MTT结果表明，DTX-PGD纳米粒对4T1细胞较多烯紫杉醇溶液具有更强的杀伤作用。结论 PGD树状大分子可以作为一种有效的稳定剂应用到多烯紫杉醇纳米粒的制备中，DTX-PGD纳米粒有望作为一种新型的药物输送系统应用到癌症的临床治疗中。

Objective To prepare docetaxel (DTX) nanoparticles with the codendrimer PGD as a stabilizer in order to enhance the solubility and bioavailability of DTX. Methods The DTX-PGD nanoparticles were prepared via the method of ultrasound precipitation combined high-pressure homogenization using codendrimer PAMAM-co-0.25OEG (PGD) as a stabilizer. The particle size and Zeta potential of DTX-PGD nanoparticles were measured by dynamic light scattering; The stability of DTX-PGD nanoparticles in normal saline solution, 5% glucose, PBS, and plasma were investigated at 37℃, along with the hemolysis rate of the nanoparticles. X-ray powder diffraction was used to detect the state of DTX in DTX-PGD nanoparticles. The in vitro release behavior of DTX-PGD nanoparticles was measured via dialysis method. MTT assay was employed to investigate the cytotoxicity of DTX-PGD nanoparticles towards 4T1 cells. Results The drug loading capacity (DL%) of DTX-PGD nanoparticles was 65.7%, the solubility of DTX was increased to 1.6 mg/mL. The mean diameter of nanoparticles was 270.4 nm, the PDI was 0.128, and the Zeta potential was 28.6 mV. The DTX-PGD nanoparticles were stable in glucose and plasma. The nanoparticles exhibited schistose morphology in SEM. The XRD spectra of DTX-PGD nanoparticles showed that DTX was present as crystal morphology in the nanoparticles. The release of DTX from nanoparticles was detected in PBS+0.5% SDS release medium and presented obvious controlled release behavior.There was no hemolytic phenomenon which means they were suitable for iv administration. MTT results showed that the nanoparticles exhibited higher cytoxicity for 4T1 cells compared with DTX solution. Conclusion In summary, PGD may be an effective stabilizer for the preparation of DTX-PGD nanoparticles and DTX-PGD nanoparticle is a promising drug delivery system for DTX application in clinic.

国家自然科学基金（NO. 21444003）；北京协和医学院青年基金（NO. 33320140184）资助项目