| Summary: | There is widespread interest in developing agents to modify tumor hypoxia in head and neck squamous cell carcinomas (HNSCC). Here, we report on the synthesis, characterization, and potential utility of ultra-small NaYF<sub>4</sub>:Nd<sup>3+</sup>/NaGdF<sub>4</sub> nanocrystals coated with manganese dioxide (usNP-MnO<sub>2</sub>) for spatiotemporal modulation of hypoxia in HNSCC. Using a dual modality imaging approach, we first visualized the release of Mn<sup>2+</sup> using T1-weighted magnetic resonance imaging (MRI) and modulation of oxygen saturation (%sO<sub>2</sub>) using photoacoustic imaging (PAI) in vascular channel phantoms. Combined MRI and PAI performed in patient-derived HNSCC xenografts following local and systemic delivery of the hybrid nanoparticles enabled mapping of intratumoral nanoparticle accumulation (based on T1 contrast enhancement) and improvement in tumor oxygenation (increased %sO<sub>2</sub>) within the tumor microenvironment. Our results demonstrate the potential of hybrid nanoparticles for the modulation of tumor hypoxia in head and neck cancer. Our findings also highlight the potential of combined MRI-PAI for simultaneous mapping nanoparticle delivery and oxygenation changes in tumors. Such imaging methods could be valuable in the precise selection of patients that are likely to benefit from hypoxia-modifying nanotherapies.
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