Department of Experimental Molecular Imaging, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
Eur J Pharm Sci. 2012 Mar 12;45(4):421-8. doi: 10.1016/j.ejps.2011.08.028. Epub 2011 Sep 1.
Over the past few decades, many different types of nanomedicines have been evaluated, both in vitro and in vivo. In general, nanomedicines are designed to improve the in vivo properties of low-molecular-weight (chemo-) therapeutic drugs, i.e. their biodistribution and the target site accumulation, and to thereby improve the balance between their efficacy and toxicity. A significant number of studies have also addressed the in vitro properties of nanomedicines, showing e.g. their ability to overcome cellular multidrug resistance (MDR). Particularly promising results in this regard have been reported for 'pharmacologically active' carrier materials, such as Pluronics, which are able to directly inhibit drug efflux pumps and other cellular detoxification mechanisms. In the present report, we have set out to evaluate the ability of classical (and pharmacologically inactive) carrier materials to overcome MDR. To this end, four different drug-sensitive and drug-resistant cancer cell lines were treated with increasing concentrations of free doxorubicin, of polymer-bound doxorubicin, of micellar doxorubicin and of liposomal doxorubicin, and resistance indices (IC(50) in resistant cells/IC(50) in sensitive cells) were determined. In addition, the cellular uptake of the four formulations was evaluated using fluorescence microscopy. It was found that the carrier materials did manage to overcome MDR to some extent, but that the overall benefit was quite small; only for polymer-bound doxorubicin in A431 cells, a significant (4-fold) reduction in the resistance index was observed. These findings indicate that the ability of classical nanomedicines to overcome cellular MDR should not be overestimated.
在过去几十年中，已经评估了许多不同类型的纳米药物，包括在体和离体。一般来说，纳米药物旨在改善低分子量（化学）治疗药物的体内特性，即其生物分布和靶部位积累，从而改善其疗效和毒性之间的平衡。大量研究还涉及纳米药物的体外特性，例如显示其克服细胞多药耐药性（MDR）的能力。在这方面，特别有前途的结果已报道用于“药理活性”载体材料，如 Pluronics，其能够直接抑制药物外排泵和其他细胞解毒机制。在本报告中，我们着手评估经典（和药理上无活性）载体材料克服 MDR 的能力。为此，用递增浓度的游离阿霉素、聚合物结合的阿霉素、胶束阿霉素和脂质体阿霉素处理四种不同的药物敏感和耐药癌细胞系，并确定耐药指数（耐药细胞中的 IC50/敏感细胞中的 IC50）。此外，还使用荧光显微镜评估了四种制剂的细胞摄取。结果发现，载体材料确实在一定程度上克服了 MDR，但总体益处相当小；只有在 A431 细胞中，聚合物结合的阿霉素的耐药指数才观察到显著（4 倍）降低。这些发现表明，不应高估经典纳米药物克服细胞 MDR 的能力。
