Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, PR China.
Bioconjug Chem. 2011 Oct 19;22(10):1939-45. doi: 10.1021/bc200139n. Epub 2011 Sep 9.
Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. The intracellular accumulation of drug and the intracellular release of drug molecules from the carrier could be the most important barriers for nanoscale carriers in overcoming MDR. We demonstrated that the redox-responsive micellar nanodrug carrier assembled from the single disulfide bond-bridged block polymer of poly(ε-caprolactone) and poly(ethyl ethylene phosphate) (PCL-SS-PEEP) achieved more drug accumulation and retention in MDR cancer cells. Such drug carrier rapidly released the incorporated doxorubicin (DOX) in response to the intracellular reductive environment. It therefore significantly enhanced the cytotoxicity of DOX to MDR cancer cells. It was demonstrated that nanoparticular drug carrier with either poly(ethylene glycol) or poly(ethyl ethylene phosphate) (PEEP) shell increased the influx but decreased the efflux of DOX by the multidrug resistant MCF-7/ADR breast cancer cells, in comparison with the direct incubation of MCF-7/ADR cells with DOX, which led to high cellular retention of DOX. Nevertheless, nanoparticles bearing PEEP shell exhibited higher affinity to the cancer cells. The shell detachment of the PCL-SS-PEEP nanoparticles caused by the reduction of intracellular glutathione significantly accelerated the drug release in MCF-7/ADR cells, demonstrated by the flow cytometric analyses, which was beneficial to the entry of DOX into the nuclei of MCF-7/ADR cells. It therefore enhanced the efficiency in overcoming MDR of cancer cells, which renders the redox-responsive nanoparticles promising in cancer therapy.
多药耐药性（MDR）是癌症化疗成功的主要障碍。药物在细胞内的积累和药物分子从载体中的细胞内释放可能是纳米载体克服 MDR 的最重要障碍。我们证明，由单硫键桥联的聚（ε-己内酯）和聚（乙基乙烯基磷酸酯）（PCL-SS-PEEP）组成的氧化还原响应胶束纳米药物载体在多药耐药性癌细胞中实现了更多的药物积累和保留。这种药物载体在响应细胞内还原环境时迅速释放所包含的阿霉素（DOX）。因此，它显著增强了 DOX 对多药耐药性癌细胞的细胞毒性。研究表明，与 DOX 直接孵育 MCF-7/ADR 细胞相比，具有聚乙二醇（PEG）或聚（乙基乙烯基磷酸酯）（PEEP）壳的纳米药物载体增加了 DOX 的流入，但减少了 DOX 的流出，从而导致 DOX 在细胞内的高保留。然而，带有 PEEP 壳的纳米颗粒对癌细胞表现出更高的亲和力。细胞内谷胱甘肽还原导致 PCL-SS-PEEP 纳米颗粒的外壳脱落，显著加速了 MCF-7/ADR 细胞中的药物释放，通过流式细胞术分析证明，这有利于 DOX 进入 MCF-7/ADR 细胞的细胞核。因此，它提高了克服癌细胞 MDR 的效率，使氧化还原响应性纳米颗粒在癌症治疗中具有广阔的应用前景。
