Development and characterisation of a thermoreversible sol-gel for intranasal delivery of MRI and PET imaging agents

Central nervous system disorders remain particularly difficult to manage due to the blood-brain barrier preventing effective uptake and distribution of most therapeutic and diagnostic agents to brain parenchyma. Intranasal delivery using thermoreversible sol-gels is a non-invasive strategy proposed to bypass the blood-brain barrier, enhance mucosal residence, and enable sustained release of an agent. This study investigated poloxamer-based sol-gels for the intranasal delivery of Gd-DTPA for MRI and [⁶⁴Cu]Cu²⁺ for PET. Formulations containing a blend of poloxamers and hydroxypropyl methylcellulose were optimised for gelation temperature, rheology, pH, and osmolality. In vitro release studies were performed using the Franz diffusion apparatus, ICP-MS analysis, and real-time imaging on a hybrid PET/MRI system. Gd-DTPA release was characterised by erosion-controlled kinetics, best described by the Korsmeyer-Peppas and zero-order models (R² = 0.95). MRI relaxometry confirmed sustained release, with cumulative values of ∼19 % (T1-based) and ∼13 % (T2-based) at ∼9 h. ICP-MS indicated cumulative release of ∼17 %, with a ∼2 percentage-point difference attributed to small changes in setup and mixing. The [⁶⁴Cu]Cu²⁺ release followed diffusion-dominated kinetics, with Higuchi and Korsmeyer-Peppas models providing the best fit (R² = 0.92). Thus, within the sol-gel matrix, the MRI agent serves as an erosion-controlled payload, whereas the PET agent behaves as a diffusion-controlled payload, illustrating how the amount and hydrodynamic properties of an imaging agent can be exploited to tailor release mechanisms and imaging windows. These results demonstrate that sol-gels can sustain the release of chemically distinct imaging agents. To the best of our knowledge, this is the first in vitro study to directly compare an MRI contrast agent and a PET radionuclide embedded within a single intranasal thermoreversible sol-gel platform. Hence, it provides in vitro proof-of-concept for future real-time nose-to-brain imaging of the central nervous system.