Selenium Containing Dendritic Prodrugs with Anticancer Activity

Reactive oxygen species (ROS) are free radicals containing oxygen that react with other cell molecules. Under normal physiological conditions cells control the generation of ROS through the presence of natural scavenging systems. However, elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers where they promote many aspects of tumor development and progression. Among all redox modulating compounds, selenium derivatives have gained substantial attention due to their promising chemotherapeutic potential and redox modulating capacity.¹ These properties provide selenium compounds with increased selectivity for cancer cells overcoming one of main drawbacks of the current chemotherapeutic treatments. In the development of new treatments to reduce chemotherapy induced side effects, dendrimers with nanometric size arise as the ultimate unimolecular precision polymers in the biomedical field with the capability of accumulating in the tumor environment due to the enhanced permeability and retention (EPR) effect. Previously our group reported the synthesis of polyester dendrimers with internal disulfide functionalities that collapse inside human lung carcinoma cells and alter the redox balance by upregulating oxidative stress.² In this work, funded by the Marie Sklodowska-Curie Actions programme, selenium-containing polyester dendrimers up to third generation have been synthesized and characterized. These dendrimers contain a skeleton based on 2,2 bis-(hydroxymethyl)propionic acid (bis-MPA) with imbedded selenium functionalities. The presence of peripheral functionalities allows for the post-functionalization with interesting molecules from a biological point of view such as polyethylene glycol (PEG) or cationic groups that could potentiate the water solubility, half-life or even the anticancer potential. Due to the presence of selenium, the synthesized dendritic polymers show faster degradation profile intracellularly than extracellularly where the concentration of glutathione is considerably less. Additionally, the presence of ester bonds makes those systems responsive to pH, where at higher pHs the dendritic structures undergo degradation through a depolymerization mechanism from the exterior to the most inner layers as previously observed for traditional bis-MPA dendrimers.³ <i>In vitro</i> preliminary studies indicate a promising anticancer potential towards breast cancer cells for the synthesized selenium-based dendrimers. Additionally, the presence of selenium promotes the <i>in vitro</i> selectivity for breast cancer cells compared to non-cancer cells, in contrast to what has been observed for analogue dendrimers without selenium used as controls.<br/><br/><i>References:</i><br/>(1) Kursvietiene, L., Mongirdiene, A., Bernatoniene, J., Sulinskiene, J., Staneviciene, I. <i>Antioxidants.</i> <b>2020</b>, 9(1), 80.<br/>(2) Andren, O. C. J., Fernandes A. P., Malkoch, M. <i>J. Am. Chem. Soc</i>. <b>2017</b>, 139, 17660−1766.<br/>(3) Feliu, N., Walter, M. V., Montañez, M. I., Kunzmann, A., Hult, A., Nyström, A., Malkoch, M., Fadeel, B. <i>Biomaterials</i>. <b>2012</b>, 33, 1970e1981.