Department of Biomedical Engineering, McGill University, 3775 University Street, Montreal, Quebec, Canada H3A 2B4.
Bioconjug Chem. 2011 Feb 16;22(2):235-43. doi: 10.1021/bc100374p. Epub 2010 Dec 28.
Ultrasmall (mean diameter, 2.7 nm) gold nanoparticles conjugated to doxorubicin (Au-Dox) are up to 20-fold more cytotoxic to B16 melanoma cells than the equivalent concentration of doxorubicin alone, and act up to six times more quickly. Ultrasmall Au-Dox enters the cell endocytic vesicles and is also seen free in the cytoplasm and nuclei. This is in distinct contrast to larger particles reported in previous studies, which are excluded from the nucleus and which show no increased toxicity over Dox alone. Cell death with Au-Dox is confirmed to be apoptotic by TUNEL staining and ultrastructural examination using transmission electron microscopy. To further explore the mechanism of action, two other cell lines were examined: HeLa cells which are highly sensitive to Dox, and HeLa cells overexpressing Bcl-2 which show impaired apoptosis and Dox resistance. Interestingly, the Dox-sensitive cells show a slightly decreased sensitivity to Au-Dox relative to Dox alone, whereas the Dox-resistant cells are not resistant to Au-Dox. These results have implications for the design of chemotherapeutic nanoparticles, suggesting that it is possible to selectively target apoptosis-resistant cancer cells while at the same time reducing cytotoxicity to normal cells.
与等浓度的游离阿霉素相比，连接到阿霉素的超小（平均直径 2.7nm）金纳米颗粒对 B16 黑色素瘤细胞的细胞毒性高 20 倍，作用速度快 6 倍。超小的 Au-Dox 进入细胞内吞小泡，也可在细胞质和细胞核中观察到游离状态。这与以前研究中报道的较大颗粒形成鲜明对比，以前研究中的较大颗粒被排除在细胞核之外，并且与游离阿霉素相比没有增加毒性。TUNEL 染色和透射电子显微镜的超微结构检查证实，Au-Dox 诱导的细胞死亡为凋亡。为了进一步探讨作用机制，还研究了另外两种细胞系：对 Dox 高度敏感的 HeLa 细胞和过表达 Bcl-2 的 HeLa 细胞，后者表现出凋亡受损和 Dox 耐药。有趣的是，Dox 敏感细胞对 Au-Dox 的敏感性略低于单独使用 Dox，而 Dox 耐药细胞对 Au-Dox 没有耐药性。这些结果对化疗纳米颗粒的设计具有重要意义，表明有可能选择性地靶向凋亡抵抗的癌细胞，同时降低对正常细胞的细胞毒性。
