Hami Zahra, Rezayat Seyed Mahdi, Gilani Kambiz, Amini Mohsen, Ghazi-Khansari Mahmoud
Department of Toxicology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran.
Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
J Pharm Pharmacol. 2017 Feb;69(2):151-160. doi: 10.1111/jphp.12675. Epub 2017 Jan 3.
The pH-sensitive doxorubicin (DOX)-conjugated and docetaxel (DTX)-conjugated poly(lactic acid)-poly(ethylene glycol)-folate (PLA-PEG-FOL)-based polymeric micelles were developed and characterized in this study.
The drugs were released from the micelles (particle size, ~185 nm) in a pH-dependent manner. The drug-conjugated PLA-PEG-FOL micelles showed higher cellular uptake than nontargeting ones. Single agent and combination in-vitro cytotoxicity studies were also performed using the two drugs in both free and their micellar forms in SKOV3 human ovarian cancer cells using three different cytotoxicity assays. Like the free drugs, DOX-conjugated and DTX-conjugated targeting micelles showed significant cytotoxic effects in SKOV3 cell line. Moreover, the drug-conjugated targeting micelles improved cytotoxicity compared to the FOL-free ones. Different ratios of IC of free drugs were used for combination therapy, and synergistic, additive or antagonistic effects were evaluated. The synergistic effect was observed in specific DOX : DTX mixing ratios, which result in the increase in therapeutic efficacy using low doses of each test compound without formulation related side effects.
The prepared micelles may provide appropriate delivery systems for doxorubicin and docetaxel in both single and combination therapies.
本研究开发并表征了基于pH敏感的阿霉素（DOX）共轭和多西他赛（DTX）共轭的聚乳酸-聚乙二醇-叶酸（PLA-PEG-FOL）聚合物胶束。
药物以pH依赖的方式从胶束（粒径约185nm）中释放。药物共轭的PLA-PEG-FOL胶束比非靶向胶束表现出更高的细胞摄取率。还使用三种不同的细胞毒性测定方法，在SKOV3人卵巢癌细胞中，以游离形式和胶束形式对这两种药物进行了单药和联合体外细胞毒性研究。与游离药物一样，DOX共轭和DTX共轭的靶向胶束在SKOV3细胞系中显示出显著的细胞毒性作用。此外，与不含叶酸的胶束相比，药物共轭的靶向胶束提高了细胞毒性。游离药物的不同IC比例用于联合治疗，并评估协同、相加或拮抗作用。在特定的DOX:DTX混合比例下观察到协同效应，这导致使用低剂量的每种测试化合物时治疗效果增加，而无制剂相关的副作用。
所制备的胶束可为阿霉素和多西他赛的单药治疗及联合治疗提供合适的给药系统。
