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Mitochondria-Targeted Polyamidoamine Dendrimer–Curcumin Construct for Hepatocellular Cancer Treatment
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2020-11-18 , DOI: 10.1021/acs.molpharmaceut.0c00566
Shahla Kianamiri 1 , Ali Dinari 1 , Majid Sadeghizadeh 1, 2 , Mohsen Rezaei 3 , Bahram Daraei 4 , Noor El-Huda Bahsoun 5 , Alireza Nomani 6
Affiliation  

Mitochondrial malfunction plays a crucial role in cancer development and progression. Cancer cells show a substantially higher mitochondrial activity and greater mitochondrial transmembrane potential than normal cells. This concept can be exploited for targeting cytotoxic drugs to the mitochondria of cancer cells using mitochondrial-targeting compounds. In this study, a polyamidoamine dendrimer-based mitochondrial delivery system was prepared for curcumin using triphenylphosphonium ligands to improve the anticancer efficacy of the drug in vitro and in vivo. For the in vitro evaluations, various methods, such as viability assay, confocal microscopy, flow cytometry, reactive oxygen species (ROS), and real-time polymerase chain reaction analyses, were applied. Our findings showed that the targeted-dendrimeric curcumin (TDC) could successfully deliver and colocalize the drug to the mitochondria of the cancer cells, and selectively induce a potent apoptosis and cell cycle arrest at G2/M. Moreover, at a low curcumin dose of less than 25 μM, TDC significantly reduced adenosine triphosphate and glutathione, and increased the ROS level of the isolated rat hepatocyte mitochondria. The in vivo studies on the Hepa1-6 tumor-bearing mice also indicated a significant tumor suppression effect and the highest median survival days (Kaplan–Meier survival estimation and log-rank test) after treatment with the TDC construct compared to the free curcumin and untargeted construct. Besides its targeted nature and safety, the expected improved solubility and stability represent the prepared targeted-dendrimeric construct as an up-and-coming candidate for cancer treatment. The results of this study emphasize the promising route of mitochondrial targeting as a practical approach for cancer therapy, which can be achieved by optimizing the delivery method.

中文翻译:

用于肝细胞癌治疗的线粒体靶向聚酰胺胺树枝状聚合物-姜黄素构建体

线粒体功能障碍在癌症的发展和进展中起着至关重要的作用。癌细胞显示出比正常细胞显着更高的线粒体活性和更大的线粒体跨膜电位。这一概念可用于使用线粒体靶向化合物将细胞毒性药物靶向癌细胞的线粒体。在这项研究中,使用三苯基鏻配体为姜黄素制备了一种基于聚酰胺胺树枝状聚合物的线粒体递送系统,以提高药物的体外和体内抗癌功效。对于体外评估,应用了各种方法,例如活力测定、共聚焦显微镜、流式细胞术、活性氧 (ROS) 和实时聚合酶链反应分析。我们的研究结果表明,靶向树枝状姜黄素 (TDC) 可以成功地将药物递送并共定位到癌细胞的线粒体,并在 G2/M 选择性诱导有效的细胞凋亡和细胞周期停滞。此外,在低于 25 μM 的低姜黄素剂量下,TDC 显着降低了三磷酸腺苷和谷胱甘肽,并增加了分离的大鼠肝细胞线粒体的 ROS 水平。对荷有 Hepa1-6 肿瘤的小鼠的体内研究还表明,与游离姜黄素和非靶向构造。除了其有针对性的性质和安全性,预期改善的溶解度和稳定性代表制备的靶向树枝状构建体作为癌症治疗的新兴候选者。这项研究的结果强调了线粒体靶向作为一种实用的癌症治疗方法的有希望的途径,这可以通过优化递送方法来实现。
更新日期:2020-12-07
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