多柔比星与槲皮素联载胶束逆转乳腺癌多药耐药研究

Study on Doxorubicin and Quercetin Co-encapsulated Micelles for Reversing Multidrug Resistance of Breast Cancer

目的:以聚乙二醇-聚乳酸-羟基乙酸共聚物(PEG-PLGA)为载体,构建多柔比星(DOX)与槲皮素(QUE)的PEG-PLGA/DOX+QUE联载胶束,并对其逆转乳腺癌多药耐药效果进行评价。方法:采用透析袋法制备载PEG-PLGA/DOX+QUE联载胶束,并对该药物递送系统的理化性质、体外释放特性、药效学以及安全性进行系统评价。结果:所制得的PEG-PLGA/DOX+QUE联载胶束平均粒径为(58. 2±5. 6) nm,联载胶束中DOX与QUE的载药量分别为(9. 12±0. 97)%和(8. 34±0. 92)%;细胞摄取实验结果表明联载胶束中的QUE可有效抑制乳腺癌耐药(MCF-7/ADR)细胞对DOX的外排作用,且PEGPLGA/DOX+QUE联载胶束对MCF-7/ADR细胞的细胞毒性显著大于游离DOX、游离DOX+QUE及PEG-PLGA/DOX胶束;体内药效学结果显示PEG-PLGA/DOX+QUE联载胶束可有效抑制荷瘤小鼠皮下瘤生长,并且显示出良好的生物相容性。结论:PEG-PLGA/DOX+QUE联载胶束可有效逆转乳腺癌多药耐药,增强对耐药肿瘤细胞的毒性作用,是一种有应用前景的抗肿瘤药物递送系统。

Objective: To construct doxorubicin and quercetin( DOX + QUE) loaded micelles and investigate the reversal effects on breast cancer multidrug resistance with polyethylene glycol and poly( lactic-co-glycolic acid)( PEG-PLGA) as the carrier. Methods: PEG-PLGA/DOX + QUE micelles were prepared using the dialysis method,and then characterized by the physicochemical parameters,drug release profile,pharmacodynamics and safety. Results: The average particle size of PEG-PLGA/DOX + QUE micelles was(58. 2 ± 5. 6) nm. The drug loading rate of DOX and QUE was(9. 12 + 0. 97) % and(8. 34 + 0. 92) %,respectively. The results of cellular uptake test showed that QUE could effectively reduce DOX efflux from MCF-7/ADR cells,and cytotoxicity of PEG-PLGA/DOX+ QUE micelles against MCF-7/ADR cells was significantly stronger than that of free DOX,free DOX + QUE and PEG-PLGA/DOX micelles. The results of pharmacodynamics in vivo showed that PEG-PLGA/DOX + QUE micelles could effectively inhibit the growth of subcutaneous tumor in tumor-bearing mice with good biocompatibility. Conclusion: PEG-PLGA/DOX + QUE micelles can effectively reverse multidrug resistance and cytotoxicity for cancer cells,which is a promising antitumor drug delivery system.