氧化还原反应性糖脂纳米载体的顺序疗法分别递送siRNA和阿霉素以克服多药耐药性,International Journal of Pharmaceutics

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氧化还原反应性糖脂纳米载体的顺序疗法分别递送siRNA和阿霉素以克服多药耐药性
International Journal of Pharmaceutics ( IF 5.3 ) Pub Date : 2017-12-01 , DOI: 10.1016/j.ijpharm.2017.10.036
Tingting Meng , Binbin Lu , Shihong Shao , Ming Yuan , Xuan Liu , Hong Yuan , Xuan Huang , Fuqiang Hu

P-糖蛋白（P-gp）是在多药耐药性肿瘤细胞上过表达的主要外排转运蛋白，负责将药物泵出。如果在P-gp水平低的情况下使用抗肿瘤药物，可能会获得令人满意的治疗效果。因此，P-gp下调siRNA（siMDR1）和阿霉素（DOX）用于消除多药耐药性乳腺癌细胞（MCF-7 / ADR）。氧化还原反应的糖脂共轭物（CSO-ss-SA）用于凝聚siRNA（CSO-ss-SA / siRNA）并分别封装DOX（CSO-ss-SA / DOX）。他们对肿瘤细胞高度还原的环境做出了反应，并迅速释放了有效载荷。CSO-ss-SA / siMDR1使MDR1基因沉默，并导致P-gp瞬时降低。随后，当P-gp降至最低水平时，便交付了DOX配方（CSO-ss-SA / DOX或DOX·HCl）。CSO-ss-SA / siMDR1预处理后，CSO-ss-SA / DOX和DOX·HCl对MCF-7 / ADR细胞的细胞毒性分别是单独用DOX·HCl处理的细胞毒性的6.4或3.4倍，表现出增加的趋势。耐药细胞对细胞毒素的敏感性和最大的治疗效果。这些结果表明，CSO-ss-SA / siRNA和CSO-ss-SA / DOX的顺序治疗策略具有实现最佳克服多药耐药性的潜力。

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Sequential therapy with redox-responsive glucolipid nanocarrier separately delivering siRNA and doxorubicin to overcome multidrug resistance

P-glycoprotein (P-gp) is a major efflux transporter overexpressed on multidrug resistant tumor cells and responsible for pumping drugs out. If anti-tumor drugs are given when P-gp level is low, satisfactory treatment efficiency may be achieved. Thus, a P-gp down-regulating siRNA (siMDR1) and doxorubicin (DOX) were applied to eliminate multidrug resistant breast cancer cells (MCF-7/ADR). A redox-responsive glucolipid conjugate (CSO-ss-SA) was used to condense siRNA (CSO-ss-SA/siRNA) and encapsulate DOX (CSO-ss-SA/DOX) separately. They responded to the high reducing environment of tumor cells and fast released the payload. CSO-ss-SA/siMDR1 silenced MDR1 gene and resulted in a transient decrease of P-gp. Sequentially, DOX formulation (CSO-ss-SA/DOX or DOX·HCl) was delivered when P-gp was reduced to the lowest level. After pretreatment by CSO-ss-SA/siMDR1, cytotoxicity of CSO-ss-SA/DOX and DOX·HCl against MCF-7/ADR cells were 6.4 or 3.4-fold respectively of that treated by DOX·HCl alone, which exhibited increased cytotoxin sensitivity of drug resistant cells and maximized therapeutic outcomes. These results revealed that the sequential treatment strategy of CSO-ss-SA/siRNA and CSO-ss-SA/DOX hold potential in achieving an optimal overcoming multidrug resistance efficiency.

更新日期：2017-12-01

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