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HuH-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2.131 μg·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0.000 16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。
Abstract
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 HuH-7 hepatoma cells.The IC50 of nanomicelle and free DOX were 3.596 and 2.131 μg·mL-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 were 69.72% and 52.40%, respectively, which were higher than those of free DOX (52.27%). P values are 0.000 16 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.
关键词
乳糖-多柔比星 /
纳米胶束 /
靶向 /
药效 /
安全性
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Key words
lactose-doxorubicin /
nanomicelle /
targeting /
pharmacodynamics /
safety evaluation
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中图分类号：
R944
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参考文献
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脚注
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基金
国家重点研发计划项目资助(2016YFA0201503)
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