目的 制备卡巴他赛纳米脂质载体(cabazitaxel nanostructured lipid carriers, Cbz-NLCs),对处方进行优化,对制剂进行质量评价,并初步考察其体外抗肿瘤活性。方法 采用乳化蒸发-低温固化法制备Cbz-NLCs,响应面Box-Behnken Design筛选最优处方,并制成冻干粉。采用Malvern激光粒度仪、透射电镜、差示扫描量热(differential scanning calorimeter,DSC)考察该制剂冻干粉的理化性质,采用透析法考察其体外释放规律,在低温条件下考察其初步稳定性,通过细胞毒性实验初步考察其体外抗肿瘤活性。结果 按优化条件制备的Cbz-NLCs冻干粉呈球形或类球形,分布均匀,平均粒径为(186.9±3.6)nm,多分散系数(polydispersity index,PDI)为(0.213±0.003),Zeta电位为(-40.2±0.3)mV,包封率为(94.35±1.17)%,载药量为(1.11±0.32)%。DSC结果表明,卡巴他赛以无定形态存在于纳米脂质载体内。体外释放结果显示,Cbz-NLCs在8 h时释药44.48%。初步稳定性实验结果表明,Cbz-NLCs冻干粉在4 ℃低温条件下放置90 d内具有良好的稳定性。细胞学实验表明,与游离的卡巴他赛原料药相比,Cbz-NLCs对鼠源乳腺癌4T1细胞具有增强的细胞毒性。结论 采用乳化蒸发-低温固化法制备的Cbz-NLCs粒径较小,分布均匀,包封率高,具有明显的药物缓释作用和增强的细胞毒性。

OBJECTIVE To prepare the cabazitaxel-loaded nanostructured lipid carriers(Cbz-NLCs), optimize the prescription, evaluate their pharmaceutical property, and study their anti-tumor activity. METHODS The Cbz-NLCs were prepared by using emulsion evaporation-low temperature curing method, and the optimum prescription was screened by response surface of Box-Behnken Design, the Cbz-NLCs were finally made into freeze-dried powder. The particle size and distribution were measured by Malvern laser granulometer. The morphology was observed under transmission electron microscope(TEM). Differential scanning calorimeter(DSC) was used for phase analysis. The in vitro release behavior was determined by the dialysis method. The preliminary stability was studied at low temperature. Cytotoxicity assay was employed to evaluate the anti-tumor activity. RESULTS The TEM images showed that the as-prepared freeze-dried Cbz-NLCs under the optimum conditions were spherical or quasi-spherical in shape, and exhibited good dispersibility. The average particle size of Cbz-NLCs was (186.9±3.6) nm with a polydispersity index(PDI) of (0.213±0.003), and their Zeta potential was (-40.2±0.3 )mV. The encapsulation efficiency of Cbz loaded into Cbz-NLCs was (94.35±1.17)%,and the drug-loading capacity was (1.11±0.32)%. DSC results indicated that the drug was dispersed in NLCs in an amorphous state. The in vitro drug release of Cbz-NLCs in 8 h was 44.48%. The preliminary stability test results demonstrated the good stability of freeze-dried Cbz-NLCs under 4 ℃ within 90 d of storage. The cytotoxicity of Cbz-NLCs on 4T1 cells (murine-derived breast cancer cells) was significantly stronger than that of free Cbz. CONCLUSION The Cbz-NLCs prepared by using emulsion evaporation-low temperature curing method exhibited small and uniform particle size, good dispersibility, high encapsulation efficiency, sustained drug release behavior, and enhanced cytotoxicity.