Metronidazole-functionalized iron oxide nanoparticles for molecular detection of hypoxic tissues

Being crucial under several pathological conditions, tumors, and tissue engineering, the MRI tracing of hypoxia within cells and tissues would be improved by the use of nanosystems allowing for direct recognition of low oxygenation and further treatment-oriented development. In the present study, we functionalized dendron-coated iron oxide nanoparticles (dendronized IONPs) with a bioreductive compound, a metronidazole-based ligand, to specifically detect the hypoxic tissues. Spherical IONPs with an average size of 10 nm were obtained and then decorated with the new metronidazole-conjugated dendron. The resulting nanoparticles (metro-NPs) displayed negligible effects on cell viability, proliferation, and metabolism, in both monolayer and 3D cell culture models, and a good colloidal stability in bio-mimicking media, as shown by DLS. Overtime quantitative monitoring of the IONP cell content revealed an enhanced intracellular retention of metro-NPs under anoxic conditions, confirmed by the in vitro MRI of cell pellets where a stronger negative contrast generation was observed in hypoxic primary stem cells and tumor cells after labeling with metro-NPs. Overall, these results suggest desirable properties in terms of interactions with the biological environment and capability of selective accumulation into the hypoxic tissue, and indicate that metro-NPs have considerable potential for the development of new nano-platforms especially in the field of anoxia-related diseases and tissue engineered models.