Fluorescent sulfur- and nitrogen-doped carbon nanodots (CDs) are zero-dimensional nanoparticles that mediate ROS production in cancer cells, displaying inherent anticancer properties. Thus, they have been proposed as nanotheranostic tools useful in image-guided cancer therapy. Here, it is shown that cancerous cells (high PDE-5 expression) receiving sildenafil delivered by CDs-based nanostructures promote positive reinforcement of PDE-5-mediated cell death via the overexpression of genes involved in the production of ROS.
The regioselective Huisgen cycloaddition between azide-β-cyclodextrin and CDs-alkyne was used to synthetize homogeneous nanostructures, named CDs-PEG4-β-Cdx, consisting of CDs functionalized at the surface with β-cyclodextrins capable of including high amount drugs such as sildenafil (>20 % w/w), and releasing them in a controlled manner. It was investigated how CDs-PEG4-β-Cdx bearing sildenafil enter cells, enhancing ROS production and cell death specifically in cancer cells overexpressing PDE-5. These nanoplatforms go beyond the bounds of EPR-based nanomedicines in which carriers are conceived as inert vehicles of toxic drugs. The findings enable the development of smart anticancer nanoplatforms that synergistically combine nanomedicines that perturb the mitochondrial electron transport chain (ROS production) with PDE-5 inhibitors which trigger oxidative stress specifically in cancer cells regardless of their location.
These results highlight the importance of engineering nanomedicines to target critical cellular mechanisms, such as the mitochondrial electron transport chain, to leverage their inherent pharmacological effects using safe drugs as enhancers.
Nicolò Mauro, Roberta Cillari, Mara Andrea Utzeri, Salvatore Costa, Gaetano Giammona, Aldo Nicosia, Gennara Cavallaro (2023) Controlled delivery of sildenafil by β-Cyclodextrin-decorated sulfur-doped carbon nanodots: a synergistic activation of ROS signaling in tumors overexpressing PDE-5. International Journal of Pharmaceutics 645, 123409. https://doi.org/10.1016/j.ijpharm.2023.123409