摘要
目的制备pH、还原双重敏感的基于聚酰胺-胺树状大分子(PAMAM)的纳米载体PSSP,用于联合携载化疗药物多柔比星(DOX)及耐药逆转剂依克立达(ELC),同时对其逆转乳腺癌多药耐药的效果进行体外评价。方法采用红外光谱FTIR对载体进行结构表征;共聚焦显微镜考察载药纳米粒在细胞内的释药情况;流式细胞术和MTT实验分别考察联合载药纳米粒对乳腺癌多药耐药的逆转作用以及体外抗肿瘤活性。结果成功制备联合载药PSSP/多柔比星/依克立达纳米粒,并通过细胞实验证实p H、还原双重敏感性。共聚焦定位实验表明载体进入细胞后主要集中在溶酶体,在其酸性条件下促发释药并扩散入核。罗丹明123外排实验表明,依克立达可显著增加MCF-7/ADR细胞内罗丹明123的蓄积量。并且PSSP/多柔比星/依克立达纳米粒对MCF-7/ADR细胞的细胞毒性显著大于游离药多柔比星以及PSSP/多柔比星纳米粒。结论多柔比星和依克立达联载纳米粒逆转乳腺癌多药耐药的效果显著提高,且对肿瘤细胞的毒性增强,是一种有应用前景的抗肿瘤药物递送系统。
OBJECTIVE To prepare a redox and pH dual sensitive nano-carrier based on PAMAM in order to co-loading chemotherapeutics doxorubicin and breast cancer muhidrug resistance reversal agent elacridar, and study their in vitro reversal effect. METHODS The infrared spectrum FTIR was used to characterize the carrier. Confocal was used to investigate the intracellular triggered drug release. The reversal effect of breast cancer muhidrug resistance and the in vitro anti-tumor activity of doxorubicin and elacridar co-loaded nanoparticles were investigated using flow cytometry and cell toxicity tests, respectively. RESULTS The doxorubicin and elacridar co-loaded nanoparticles （PSSP/DOX/ELC） were successfully prepared, and pH-redox dual sensi- tive of carrier was proved by cell experiments. And the carrier was uptaken into cells and delivery to lysosome, and drug release was triggered in the lysosome acid condition, then the released drug diffused to the nucleus. The trial of rhodamine 123 accumu- lation and efflux assay revealed that the accumulation of rhodamine 123 was notably increased after incubation of elacridar in MCF-7/ADR cells. The cytotoxicity of PSSP/DOX/ELC nanoparticles against MCF-7/ADR cell line was significantly stronger than that of either free doxorubicin or only doxorubicin loaded nanoparticles （PSSP/DOX）. CONCLUSION The reversal effect of multidrug resistance and the cytotoxicity of cancer cells were significantly enhanced by PSSP/DOX/ELC nanoparticles. PSSP/ DOX/ELC nanoparticles is a promising delivery system.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2016年第5期379-385,共7页
Chinese Pharmaceutical Journal
基金
国家自然科学基金资助项目(81302719)
江苏省自然科学基金资助项目(BK20151224)
