【作者】 刁媛媛； 韩旻； 蒋宏亮； 应晓英； 陈大为； 梁文权； 高建青；

【Author】 Yuan-Yuan Diao1,2,Min Han1,,Hong-Liang Jiang3,Xiao-Ying Ying1,Da-Wei Chen2,Wen-Quan Liang1,Jian-Qing Gao1,(1 Institute of Pharmaceutics,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 10058,P.R. China; 2 School of Pharmacy,Shenyang Pharmaceutical University,Shenyang 110016,P.R. China; 3 Department of Polymer Science and Engineering,Zhejiang University,Hangzhou 310058,P.R. China)

【机构】 浙江大学药学院制剂研究所； 沈阳药科大学药学院； 浙江大学高分子科学与工程系；

【摘要】 耐药性是肿瘤临床化疗失败的主要原因之一,本文以聚乙二醇(polyethylene glycol, PEG)-聚已内酯(polycaprolactone, PCL)和普朗尼克(Pluronic, P105)制备了携载阿霉素的复合胶束,并研究其对人白血病耐药细胞株(K562/ADR)肿瘤耐药性的抑制作用。结果显示,复合胶束可明显提高药物的体外肿瘤细胞毒性,在阿霉素12 μg/ml 浓度下,PEG-PCL/P105 复合胶束的细胞毒性较药物溶液提高了近四倍;同时与溶液组相比,阿霉素复合胶束进入细胞膜及细胞核相对迟缓、但却可维持其在细胞中的长期存留而难以被排出胞外;胶束对P-糖蛋白(Pgp)的表达无明显影响,但P105胶束和复合胶束均可显著降低细胞内线粒体膜电位以及细胞 ATP水平,进而影响 Pgp 的功能,PEG-PCL胶束对线粒体膜电位和ATP水平均无明显影响,但由于其可携载药物以胞吞形式入胞,从而避开细胞膜Pgp的识别,故最终复合胶束可通过下调线粒体膜电位和ATP水平、以及由胞吞途径入胞两种作用的发挥,抑制肿瘤细胞的耐药性。更多还原

【Abstract】 Drug-resistance of tumor cells to anticancer drugs results in the failure of clinical chemotherapy. In the present study, a novel doxorubicin (DOX)-loaded composite micelle, polyethylene glycol(PEG)-polycaprolactone (PCL)/Pluronic P105, was constructed to reverse drug-resistance of human myelogenous leukemia (K562/ADR) cells, and its modulation mechanism at cell levels was firstly investigated. PEG-PCL/P105 composite micelle exhibited almost 4 times higher cytotoxicity in K562/ADR cells than that induced by drug solution at 12 μg/ml. The confocal image showed that the DOX-encapsulated composite micelles could gradually enter the cytoplasm as well as nucleus, and stay much longer time than DOX solution. However, neither composite micelle nor single micelle decreased Pgp expression on the surface of K562/ADR cells. Further studies revealed that both P105 micelle and composite micelle could decrease ATP level significantly, which restricted the function of Pgp. The effect was due to the down regulation on mitochondrial membrane potential. On the contrary, PEG-PCL micelle has no effect on both mitochondrial membrane potential and ATP of the K562/ADR cells, but it could enter the K562/ADR cells through endocytic pathway, which help it escape the recognition of the Pgp. Therefore, the combined mechanisms of P105-mediated down regulation of mitochondrial membrane potential/ATP of the malignant cells and PEG-PCL-mediated internalization effect could be beneficial for composite micelles in treatment of drug-resistance tumor cells.更多还原