Chelator-Free ⁹⁹ ^m Tc-Labeled Yttrium Oxide Nanoparticles for Dose-Dependent Early Biodistribution Tracking in Mice

Yttrium oxide (Y₂O₃), as a rare-earth oxide nanoparticle, has potential toxicity that remains unresolved. By bridging the gap between nanomaterial development and safety assessment, this work aimed to evaluate the biodistribution of Y₂O₃ using a novel radiolabeling approach with technetium-99m (^99mTc) for real-time tracking. Different concentrations (0.4, 4, and 8 mg/mL) of Y₂O₃ were used for ^99mTc labeling and were intravenously administered to mice. <i>In vivo</i> organ biodistribution was measured <i>via</i> dynamic planar imaging and micro single-photon emission computed tomography/computed tomography (micro-SPECT/CT). Biodistribution and inductively coupled plasma mass spectrometry (ICP-MS) were conducted to quantitative tissue uptake of ^99mTc-Y₂O₃, and hematoxylin-eosin (H&E) staining were performed for histopathological evaluation. Different concentrations of ^99mTc-Y₂O₃ were successfully synthesized with a high radiochemical purity and stability. <i>In vivo</i> imaging revealed different distribution patterns with 0.4, 4, and 8 mg/mL of ^99mTc-Y₂O₃. Low-dose ^99mTc-Y₂O₃ nanoparticles rapidly cleared from pulmonary circulation, shifting to predominant hepatic-splenic accumulation. In contrast, medium and high doses demonstrated prolonged lung retention with partial redistribution to the spleen and liver. These biodistribution patterns were validated by ICP-MS, which showed a strong correlation with the ^99mTc-Y₂O₃ tracking. Histopathology revealed dose-related alveolar wall thickening and splenic white pulp expansion. This study demonstrated that ^99mTc-Y₂O₃ could be a robust tool for nanoparticle <i>in vivo</i> tracking, providing the organ distribution information for long-term toxicity studies and chronic exposure effects.