Pramanik Anup K, Palanimuthu Duraippandi, Somasundaram Kumaravel, Samuelson Ashoka G
Department of Inorganic and Physical Chemistry, ‡Department of Microbiology and Cell Biology, Indian Institute of Science , Bangalore- 560012, India.
Bioconjug Chem. 2016 Dec 21;27(12):2874-2885. doi: 10.1021/acs.bioconjchem.6b00537. Epub 2016 Dec 2.
The synthesis and anticancer activity of a copper(II) diacetyl-bis(N4-methylthiosemicarbazone) complex and its nanoconjugates are reported. The copper(II) complex is connected to a carboxylic acid group through a cleavable disulfide link to enable smart delivery. The copper complex is tethered to highly water-soluble 20 nm gold nanoparticles (AuNPs), stabilized by amine terminated lipoic acid-polyethylene glycol (PEG). The gold nanoparticle carrier was further decorated with biotin to achieve targeted action. The copper complex and the conjugates with and without biotin, were tested against HeLa and HaCaT cells. They show very good anticancer activity against HeLa cells, a cell line derived from cervical cancer and are less active against HaCaT cells. Slow and sustained release of the complex from conjugates is demonstrated through cleavage of disulfide linker in the presence of glutathione (GSH), a reducing agent intrinsically present in high concentrations within cancer cells. Biotin appended conjugates do not show greater activity than conjugates without biotin against HeLa cells. This is consistent with drug uptake studies, which suggests similar uptake profiles for both conjugates in vitro. However, in vivo studies using a HeLa cell xenograft tumor model shows 3.8-fold reduction in tumor volume for the biotin conjugated nanoparticle compared to the control whereas the conjugate without biotin shows only 2.3-fold reduction in the tumor volume suggesting significant targeting.
报道了一种铜（II）二乙酰基双（N4-甲基硫代半卡巴腙）配合物及其纳米共轭物的合成与抗癌活性。铜（II）配合物通过可裂解的二硫键连接到羧酸基团，以实现智能递送。铜配合物与由胺端基硫辛酸-聚乙二醇（PEG）稳定的高度水溶性20纳米金纳米颗粒（AuNP）相连。金纳米颗粒载体进一步用生物素修饰以实现靶向作用。测试了铜配合物以及有和没有生物素的共轭物对HeLa和HaCaT细胞的作用。它们对HeLa细胞（一种源自宫颈癌的细胞系）显示出非常好的抗癌活性，而对HaCaT细胞的活性较低。通过在谷胱甘肽（GSH，癌细胞内固有高浓度存在的还原剂）存在下二硫键连接子的裂解，证明了配合物从共轭物中的缓慢持续释放。附加生物素的共轭物对HeLa细胞的活性并不比没有生物素的共轭物更高。这与药物摄取研究一致，该研究表明两种共轭物在体外具有相似的摄取情况。然而，使用HeLa细胞异种移植肿瘤模型的体内研究表明，与对照相比，生物素共轭纳米颗粒的肿瘤体积减少了3.8倍，而没有生物素的共轭物的肿瘤体积仅减少了2.3倍，表明有显著的靶向作用。
