ROS-generating hyaluronic acid-modified zirconium diox-ide-acetylacetonate nanoparticles as a theranostic platform for the treatment of osteosarcoma

Materials able to produce free radicals have gained increasing attention for environmental and biomedical purposes. Free radicals, such as the superoxide anion (O2o-), act as secondary mes-sengers in many physiological pathways, such as cell survival. Therefore, the production of free radicals over physiological levels has been exploited in the treatment of different types of cancer, including osteosarcoma (OS). In most cases, the production of radical oxygen species (ROS) by materials is light-induced and requires the use of chemical photosensitisers, making it difficult and expensive to produce. Here, for the first time, we propose photoluminescent hybrid ZrO2-acetylacetonate nanoparticles (ZrO2-acac NPs) able to generate O2o- without light activation as an adjuvant for the treatment of OS. To increase the uptake and ROS generation in cancer cells, we modify the surface of ZrO2-acac NPs with hyaluronic acid (HA), which recognizes and binds to the surface antigen CD44 overexpressed on OS cells. Since these nanoparticles emit in the visible range, their uptake into cancer cells can be followed by a label-free approach. Overall, we show that the generation of O2o- is toxic to OS cells and can be used as an adjuvant treatment to increase the efficacy of conventional drugs.