乳糖-多柔比星偶联物纳米胶束体内药效学与安全性评价

目的合成乳糖-多柔比星两亲性小分子并制备成纳米胶束,并对其肝癌靶向性和体内抗肿瘤药效及安全性进行评价。方法采用薄膜水化法制备乳糖-多柔比星纳米胶束(lactose-doxorubicin nanomicelles,Lac-DOX NMs),采用动态光散射法测定其粒径,透射电镜观察形态;通过细胞摄取实验考察Lac-DOX NMs对肿瘤细胞的靶向性;CCK-8法测定纳米胶束和游离多柔比星的细胞毒性;构建BALB/c-nu小鼠皮下移植瘤模型,考察Lac-DOX NMs的体内抗肿瘤药效;通过血生化检测,考察该制剂对小鼠肝功能的影响以评价制剂的安全性。结果成功制备了乳糖-多柔比星纳米胶束(Lac-DOX NMs),粒径为(169.2±0.9)nm;细胞摄取实验表明,Lac-DOX NMs对Hu H-7肝癌细胞具有靶向性;细胞毒性实验测得纳米胶束和游离DOX的IC50分别为3.596和2.131μg·mL^-1;药效实验结果显示,Lac-DOX NMs能够显著抑制小鼠移植瘤的增长,Lac-DOX NMs高、低剂量的肿瘤抑制率分别为69.72%和52.40%,均高于DOX裸药(52.27%),P值分别为0.00016和0.94;血生化数据显示,与DOX相比,Lac-DOX NMs肝功能损伤情况显著降低。结论用乳糖修饰多柔比星并将其制成纳米制剂,能够显著提高多柔比星对肝癌细胞的靶向性,增强了抗肿瘤效果,同时降低多柔比星的毒副作用,提高用药安全性。

In Vivo Pharmacodynamics and Safety Evaluation of Lactose-Doxorubicin Drug-Drug Conjugate Nanomicelle

OBJECTIVE The lactose-doxorubicin amphiphilic small molecule nanomicelles and evaluate its liver cancer targeting and antitumor efficacy and safety in vivo.METHODS Lactose-doxorubicin nanomicelles(Lac-DOX NMs)were prepared by thin film hydration method.The particle size was determined by dynamic light scattering and observed by transmission electron microscopy.The effect of Lac-DOX NMs on the targeting of tumor cell was investigated by cell uptake experiments.Cytotoxicity of nanomicelles and free doxorubicin were evaluated by CCK-8 assay.The subcutaneous xenograft model of BALB/c-nu mice was constructed to investigate the anti-tumor effect of Lac-DOX NMs;the effect of the preparation on liver function of mice was examined by blood biochemical test to evaluate the safety of the preparation.RESULTS Lac-DOX NMs were successfully prepared with a particle size of(169.2±0.9)nm.Cellular uptake experiments indicated that Lac-DOX NMs are targeted to Hu H-7 hepatoma cells.The IC50 of nanomicelle and free DOX were 3.596 and 2.131μg·m L^-1,respectively.The results of pharmacodynamic experiments showed that Lac-DOX NMs could significantly inhibit the growth of transplanted tumors in mice.The tumor inhibition rates of high and low doses of Lac-DOX NMs were69.72%and 52.40%,respectively,which were higher than those of free DOX(52.27%).P values are 0.00016 and 0.94.CONCLUSION Modification of doxorubicin with lactose and its preparation into nanometer preparations can significantly improve the targeting of doxorubicin to liver cancer cells,enhance the anti-tumor effect,reduce the side effects of doxorubicin,and improve the safety of medication.