Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry, Institute of Fine Chemical Technologies, MIREA-Russian Technological University, 86 Vernadsky Avenue, 119571 Moscow, Russia.
P. Hertsen Moscow Oncology Research Institute-Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 2nd Botkinsky pr. 3, 125284 Moscow, Russia.
Int J Mol Sci. 2021 Dec 17;22(24):13563. doi: 10.3390/ijms222413563.
Photodynamic therapy (PDT) is currently one of the most promising methods of cancer treatment. However, this method has some limitations, including a small depth of penetration into biological tissues, the low selectivity of accumulation, and hypoxia of the tumor tissues. These disadvantages can be overcome by combining PDT with other methods of treatment, such as radiation therapy, neutron capture therapy, chemotherapy, etc. In this work, potential drugs were obtained for the first time, the molecules of which contain both photodynamic and chemotherapeutic pharmacophores. A derivative of natural bacteriochlorophyll a with a tin IV complex, which has chemotherapeutic activity, acts as an agent for PDT. This work presents an original method for obtaining agents of combined action, the structure of which is confirmed by various physicochemical methods of analysis. The method of molecular modeling was used to investigate the binding of the proposed drugs to DNA. In vitro biological tests were carried out on several lines of tumor cells: Hela, A549, S37, MCF7, and PC-3. It was shown that the proposed conjugates of binary action for some cell lines had a dark cytotoxicity that was significantly higher (8-10 times) than the corresponding metal complexes of amino acids, which was explained by the targeted chemotherapeutic action of the tin (IV) complex due to chlorin. The greatest increase in efficiency relative to the initial dipropoxy-BPI was found for the conjugate with lysine as a chelator of the tin cation relative to cell lines, with the following results: S-37 increased 3-fold, MCF-7 3-fold, and Hela 2.4-fold. The intracellular distribution of the obtained agents was also studied by confocal microscopy and showed a diffuse granular distribution with predominant accumulation in the near nuclear region.
光动力疗法（PDT）是目前最有前途的癌症治疗方法之一。然而，这种方法存在一些局限性，包括对生物组织的穿透深度小、积累的选择性低以及肿瘤组织缺氧。这些缺点可以通过将 PDT 与其他治疗方法结合来克服，例如放射治疗、中子俘获治疗、化学疗法等。在这项工作中，首次获得了具有潜在药用价值的药物，这些药物的分子同时包含光动力和化疗药效团。一种具有化疗活性的天然细菌叶绿素 a 的锡 IV 配合物衍生物用作 PDT 试剂。这项工作提出了一种获得具有联合作用的试剂的原始方法，其结构通过各种物理化学分析方法得到证实。使用分子建模方法研究了所提出的药物与 DNA 的结合。在体外对几种肿瘤细胞系（Hela、A549、S37、MCF7 和 PC-3）进行了生物测试。结果表明，对于某些细胞系，所提出的二元作用的缀合物具有显著更高（8-10 倍）的暗细胞毒性，这可以通过锡（IV）配合物由于叶绿素而具有靶向化疗作用来解释。与最初的二丙氧基-BPI 相比，发现具有赖氨酸作为锡阳离子螯合剂的缀合物相对于细胞系的效率提高最大，结果如下：S-37 增加了 3 倍，MCF-7 增加了 3 倍，Hela 增加了 2.4 倍。还通过共聚焦显微镜研究了获得的试剂的细胞内分布，结果显示呈弥散的颗粒状分布，主要在近核区域积累。
