Copper nanocrystalline-doped folic acid-based super carbon dots for an enhanced antitumor effect in response to tumor microenvironment stimuli

Chemodynamic therapy (CDT) is a promising cancer treatment strategy to induce tumor cell apoptosis with harmful reactive oxygen species (ROS), yet over-expression of glutathione (GSH) in the tumor microenvironment (TME) severely depletes the ROS and limits the CDT efficacy. Copper-containing materials could efficiently decrease the level of GSH in the TME. In this study, copper nanocrystalline-doped folic acid-based super carbon dots (FA-CDs@Cu^x) were prepared to realize an enhanced antitumor effect in response to tumor microenvironment stimuli. Folic acid (FA) was used as a source of carbon dots to improve the targetability of nanomaterials to tumor cells with over-expressed FA receptors. Copper existed mainly in the form of copper nanocrystals, which were embedded on the carbon core by in situ reduction of Cu²⁺ by gluconic acid. The prepared composites were found to reduce the intracellular H₂O₂ into hydroxyl radicals (˙OH) and consume GSH efficiently in tumor cells. Copper-doping enabled the CDs to absorb near-infrared light and to give a high photothermal transformation efficiency (54.3%) and high singlet oxygen atom yield (56.83%), endowing the super carbon dots with synergetic CDT/PTT/PDT functions in response to the TME and NIR stimuli, which have been investigated systematically by in vitro and in vivo biological experiments.