共载多柔比星与双硫仑Pluronic P123/F127胶束的工艺优化及逆转乳腺癌耐药性的初步研究  

Optimization of co-loaded doxorubicin and Pluronic P123/F127 mixed nanomicelles and the effects on activity and drug resistance of breast cancer cells

作　　者：任童童 尹东锋[2] REN Tong-tong;YIN Dong-feng(Department of Pharmacy,The Fifth Affiliated Hospital of Xinjiang Medical University,Urumqi 830000,China;Department of Pharmacy,General Hospital of Xinjiang Military Region,Urumqi 830000,China)

机构地区：[1]新疆医科大学第五附属医院药学部,乌鲁木齐830000 [2]新疆军区总医院药剂科,乌鲁木齐830000

出　　处：《军事医学》2022年第4期304-310,F0003,共8页Military Medical Sciences

摘　　要：目的制备一种具有固定药物比、可有效改善乳腺癌耐药性并抑制乳腺癌细胞活性的共载多柔比星与双硫仑(disulfiram)普朗尼克(Pluronic)P123/F127胶束。方法采用四甲偶氮唑蓝比色法(MTT法)筛选最佳协同药物比,薄膜水化法制备形成胶束。利用星点设计-效应面法优化的处方制备胶束,对其进行表征和体外释放评价。采用MTT实验、激光共聚焦显微镜、流式细胞仪等进行体外活性评价。结果最佳协同药物摩尔比为1∶1。最优处方为总材料量140.55 mg,总投药量9.38 mg,P123质量分数为80%。胶束粒径及Zeta电位为33.88 nm和3.29m V,在电镜下呈分布均匀的类球型。体外释放结果证实两药具有一定的p H敏感性,并最终能以固定药物比释放。与游离多柔比星的治疗效果相比,胶束使药物在肿瘤细胞核内显著积聚,MCF-7和MCF-7/ADR细胞的IC;值显著降低(1/29.65及1/94.8)。结论该研究制备的胶束工艺优良、稳定性良好,可靶向于MCF-7和MCF-7/ADR细胞,以固定比缓慢释放两种药物,发挥协同作用,显著逆转MCF-7/ADR细胞的耐药性,增强体外抗肿瘤活性。Objective To prepare micelles with a fixed drug ratio of doxorubicin and disulfiram Pluronic P123/F127,which can effectively improve drug resistance and inhibit the activity of breast cancer cells.Methods MTT was used to screen out the best synergistic drug ratio,and micelles were prepared by membrane hydration method.Then,the micelles were prepared using the optimized formulation of the star design-effect surface method,characterized and evaluated for release in vitro.Finally,MTT assay,laser confocal microscopy and flow cytometry were used to evaluate the activity in vitro.Results The best synergic drug molar ratio was 1∶1.The optimal prescription was the total material amount of 140.55 mg,the total dosage of 9.38 mg,and the P123 mass score of 80%.The particle size and Zeta potential of these micelles were 33.88 nm and 3.29 mV respectively,and they were uniformly distributed in a spheroid shape under a electron microscope.In vitro release results confirmed that the two drugs had some pH sensitivity and could be released at a fixed drug ratio.Compared with the therapeutic effect of free adriamycin,micelles caused significant accumulation of drugs in tumor nucleus,and IC;values of MCF-7 and MCF-7/ADR cells were significantly reduced by 1/29.65 and 1/94.8.Conclusion The micelles prepared in this study have excellent quality and good stability,which can target MCF-7 and MCF-7/ADR cells and release the two drugs slowly at a fixed ratio,while significantly enhancing the anti-tumor activity in vitro and reversing the drug resistance of MCF-7/ADR cells.

关 键 词：多柔比星 双硫仑 Pluronic纳米混合纳米胶束 乳腺肿瘤 抗肿瘤药 抗药性 协同抗肿瘤作用 

分 类 号：R737.9[医药卫生—肿瘤] R979.1[医药卫生—临床医学]