【摘要】 背景与目的:乳腺癌耐药是导致临床上化疗失败的一个重要原因,逆转乳腺癌耐药已经成为急待解决的问题。纳米递送系统作为药物载体有很多优点,将其作为抗癌药物载体是逆转肿瘤耐药的有效策略之一。本文研究一种新型的纳米递送系统:磷酸钙/磷脂-MPEG组装复合纳米粒对乳腺癌耐药相关蛋白(breast cancer resistance protein,BCRP)高表达的乳腺癌盐酸米托蒽醌(mitoxantrone,MIT)耐药细胞MCF-7/MIT药物摄取的影响,从而探讨该纳米递送系统对MCF-7/MIT细胞耐药性的逆转作用。方法:设计并制备了磷酸钙/磷脂组装复合纳米粒,考察了载盐酸米托蒽醌纳米粒的包封率和体外药物释放规律,定量比较了MCF-7和MCF-7/MIT细胞对载药纳米粒和游离药物的摄取,并采用激光共聚焦显微镜观察方法比较细胞摄取载药纳米粒和游离药物后药物在细胞内分布情况。结果:磷酸钙/磷脂组装复合纳米粒呈均匀的多孔球形,粒径<100nm,包载药物盐酸米托蒽醌的包封率为(89.45±0.05)%,药物释放呈初期突释和后期缓释两相。载药纳米粒与游离药物作用于细胞1h后,在MCF-7/MIT细胞内的药物摄取量前者是后者的1.89倍,在MCF-7细胞内的药物摄取量前者是后者的2.33倍,载药纳米粒可以携带药物进入细胞核,而游离药物未见明显的核内分布。结论:磷酸钙/磷脂-MPEG组装复合纳米粒可以促进乳腺癌细胞MCF-7和MCF-7/MIT细胞对抗癌药物盐酸米托蒽醌的摄取,并能携带药物进入细胞核,是一种有潜力的逆转肿瘤耐药纳米药物载体。更多还原

【Abstract】 Background and purpose:A pressing obstacle in clinical chemotherapy is drug resistance in breast cancer.A nano-delivery system,which has many advantages as a drug carrier,such as carrying anticancer drugs,can be used effectively to overcome drug resistance in tumors.This paper examined a new nano-delivery system,called calcium phosphate and glycerophosphocholine-mPEG (CAP/GPC-MPEG) composite nanoparticle and its influence on the cellular drug uptake of BCRP-over expressing mitoxantrone (MIT)-resistant breast cancer cell MCF-7/MIT.This paper will also examine its effect on overcoming drug resistance in the MCF-7/MIT cells.Methods:After the calcium phosphate and GPC-mPEG composite nanoparticles were designed and prepared,the entrapment efficiency and in vitro drug release of mitoxantrone-loaded nanoparticles were investigated.Quantitative comparisons were made between cellular uptake of drug-loaded nanoparticles and free drugs.Finally,a confocal laser scanning microscopy was used to compare the subcellular distribution of drug-loaded nanoparticles and the free drugs.Results:Calcium phosphate and GPC-mPEG composite nanoparticles were nanoporous spherical particles with diameters between 50-100 nm.The MITloaded nanoparticles have an entrapment efficiency of (89.45±0.05)%.Although the drug-loaded nanoparticles showed an initial burst of drug release,it was followed by a more sustained release.The concentration of mitoxantrone was 1.89times treated with MIT-loaded nanoparticles for 1 h compared to that treated with free mitoxantrone for 1 h in MCF7/MIT cells,and which was 2.33 times in MCF-7 cells.Fluorescent red mitoxantrone appeared in the cytoplasm and nucleus of the MCF-7 and MCF-7/MIT cells treated with MIT-loaded nanoparticles whereas it is almost undetected in both cells treated with free mitoxantrone.Conclusion:Calcium phosphate and GPC-mPEG composite nanoparticles can promote the cellular uptake and entering of mitoxantrone to the nucleus in MCF-7 and its corresponding BCRPover expressing MIT-resistant MCF-7/MIT breast cancer cell lines.This nanoparticle is a potential nano-carrier for overcoming drug resistance in tumors.更多还原