Enhanced intercellular retention activity of novel pH-sensitive polymeric micelles in wild and multidrug resistant MCF-7 cells
Enhanced intercellular retention activity of novel pH-sensitive polymeric micelles in wild and multidrug resistant MCF-7 cells
复制标题
DOI：
10.1007/s11095-007-9277-5
复制
发表时间：
2007-09-01
影响因子：
3.7
通讯作者：
Bae, You Han
中科院分区：
文献类型：
--
作者：
Mohajer, Ghazal;Lee, Eun Seong;Bae, You Han
本工作的目的是证明使用pH敏感的聚合物混合胶束（PHSM）组成的聚（L-组氨酸）（聚组氨酸）/聚组氨酸（乙二醇）（PEG）和聚（L-乳酸）（pLLA）/PEG嵌段共聚物与叶酸缀合以增加野生型和MDR肿瘤细胞中的药物保留。用细胞系研究了阿霉素（DOX）、PHSM/f和PHIM/f的蓄积和消除动力学，PHSM/f处理的细胞比PHIM/f处理的细胞的蓄积和消除动力学慢。MDR细胞与含药物PHSM/f处理30分钟保留80%的阿霉素（DOX），即使在孵育24小时后，在没有药物。另一方面，用含药物的PHIM/f处理的细胞在相同的时间段内仅保留40%的DOX。流式细胞仪和共聚焦显微镜证实了这些结果。细胞进入胶束发生通过受体介导的内吞作用使用叶酸受体。PHSM/f的pH诱导的不稳定导致药物和聚合物在整个细胞中的快速分布，这很可能是由于多聚组氨酸介导的内体破坏。这降低了药物通过胞吐作用从耐药肿瘤细胞流出的可能性。
The purpose of this work was to demonstrate the advantage of using pH-sensitive polymeric mixed micelles (PHSM) composed of poly(L-histidine) (polyHis)/poly(ethylene glycol) (PEG) and poly(L-lactic acid) (pLLA)/PEG block copolymers with folate conjugation to increase drug retention in wild-type and MDR tumor cells.Both wild-type and multidrug resistant (MDR) human breast adenocarcinoma (MCF-7) cell lines were used to investigate the accumulation and elimination of doxorubicin (DOX), PHSM with folate (PHSM/f), and pH-insensitive micelles composed of pLLA/PEG block copolymer with folate (PHIM/f).Cells treated with PHSM/f showed decelerated elimination kinetics compared to cells treated with PHIM/f. MDR cells treated with drug-containing PHSM/f for 30 min retained 80% of doxorubicin (DOX) even after incubation for 24 h in the absence of drug. On the other hand, cells treated with drug-containing PHIM/f retained only 40% of DOX within the same period of time. Flow cytometry and confocal microscopy confirmed these results.Cellular entry of the micelles occurred via receptor-mediated endocytosis using folate receptors. The pH-induced destabilization of PHSM/f led to rapid distribution of drug and polymer throughout the cells, most likely due to polyHis-mediated endosomal disruption. This reduced the likelihood of drug efflux via exocytosis from resistant tumor cells.