Quantitative in vitro PET/MRI and kinetic modelling of imaging agent release from a thermoreversible intranasal...

Intranasal phase-transforming thermoresponsive gels can prolong nasal residence and enable controlled release of diagnostic or therapeutic payloads. However, quantitative real-time release characterisation of multimodal imaging probes remains limited. Here, we developed a poloxamer-based sol-gel and established a hybrid PET/MRI framework to quantify the release of PET tracers and an activatable MnO₂ nanoflower into simulated nasal fluid. The formulations transformed from solution-to-gel at ∼ 28-29 °C with a storage modulus of 8.2-9.5  kPa attained at typical nasal cavity temperature (34 °C), while maintaining a nasal-compatible pH. PET imaging with an extended time window demonstrated diffusion-dominated release with clear size dependence: ionic [⁶⁴Cu]Cu²⁺ reached 30.0 ± 3.0 % cumulative release at ∼42  h, whereas [⁶⁴Cu]Cu-Sar-OP showed 15.6 ± 3.1 % cumulative release under the same simulated conditions. PEGylated MnO₂ nanoflowers exhibited negligible apparent release in simulated nasal fluid without reductant due to the absence of redox-triggered MnO₂ dissolution to soluble Mn²⁺ and electrolyte-induced nanoparticle aggregation trapping, which restricts diffusion out of the gel; but with GSH-supplementation, quantitative T1/T2 mapping enabled relaxivity-calibrated tracking of apparent Mn-equivalent accumulation, reaching 13.9 ± 0.7 % of the nominal loaded Mn (T1-based) at ∼24  h. The cytocompatibility of MnO₂ NFs-PEG was also evaluated in an RPMI 2650 human nasal epithelial cell model following 24-h exposure. Kinetic modelling (Higuchi and Korsmeyer - Peppas) supported diffusion-dominated transfer of the PET tracers, whereas the MnO₂ profile reflected coupled redox and transport processes under limited-GSH conditions. Overall, our integrated PET/MRI approach provides a quantitative framework for comparing in vitro depot release kinetics and informing intranasal PET/MRI formulation design; however, the findings should not be interpreted as direct evidence of mucosal retention or in vivo nose-to-brain transport.