乳糖-多柔比星偶联物纳米胶束体内药效学与安全性评价  

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

作　　者：尹春香 张刘源 高春晓 袁伟 夏桂民[3] 颜德岳[4] 陈莲珍 马洁 YIN Chun-xiang;ZHANG Liu-yuan;GAO Chun-xiao;YUAN Wei;XIA Gui-min;YAN De-yue;CHEN Lianzhen;MA Jie(School of Materials Science and Engineering,Beijing University of Chemical Technology,Beijing 100029,China;State Key Laboratory of Molecular Ontology,National Cancer Center/Cancer Hospital,Chinese Academy of Medical Science and Peking Union Medical College,Beijing 100021,China;Laboratory of Pharmaceutical Biotechnology,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing 100050,China;State Key Laboratory of Metal Matrix Composites,College of Chemistry and Chemical Technology,Shanghai Jiaotong University,Shanghai 200240,China;Department of Pharmacy,National Cancer Center/Cancer Hospital,Chinese Academy of Medical Science and Peking Union Medical College,Beijing 100021,China;Department of Biotherapy,Beijing Hospital,National Center of Gerontology,Beijing 100730,China)

机构地区：[1]北京化工大学材料科学与工程学院,北京100029 [2]国家癌症中心,中国医学科学院北京协和医学院肿瘤医院分子肿瘤学国家重点实验室,北京100021 [3]中国医学科学院北京协和医学院医药生物技术研究所制剂室,北京100050 [4]上海交通大学化学化工学院金属基复合材料国家重点实验室,上海200240 [5]国家癌症中心,中国医学科学院北京协和医学院肿瘤医院药剂科,北京100021 [6]北京医院生物治疗中心,国家老年医学中心,北京100730

出　　处：《中国药学杂志》2020年第3期206-212,共7页Chinese Pharmaceutical Journal

基　　金：国家重点研发计划项目资助(2016YFA0201503)。

摘　　要：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。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.

关 键 词：乳糖-多柔比星 纳米胶束 靶向 药效 安全性 

分 类 号：R944[医药卫生—药剂学]