Body of the abstract

Fluorine-19 magnetic resonance imaging (¹⁹F-MRI) holds considerable promise for precise cell tracking. This study investigates the MR relaxation properties of perfluorocarbon-loaded nanoparticles (PFC-NPs) co-encapsulated with a paramagnetic gadolinium (Gd) chelate (as depicted in Figure 1). Paramagnetic relaxation enhancement (PRE) operates at short distances with close proximity between the paramagnetic chelate and the ¹⁹F nuclei. We sought to understand the impact of the internal structure, specifically by comparing core-shell and multi-core NPs [1], on the PRE effect of Gd on fluorine MR signal. Our initial findings emphasize the influence of internal structural features on ¹⁹F MR relaxation times. In fractal multi-core NPs, Gd chelates affect both longitudinal (T1) and transverse (T2) relaxation times, while core-shell NPs primarily show changes in T2. Furthermore, Gd entrapped within multi-core NPs uniquely enhances ¹H MRI, benefiting from their superior water permeability compared to core-shell NPs [2]. Surprisingly, multi-core NPs exhibit pH-sensitive transverse relaxation while maintaining stability, in contrast to core-shell NPs, underscoring the value of the multi-core structure for enhancing ¹⁹F signals, as illustrated in Figure 2. The pH sensitivity was established through both ¹⁹F NMR (400 MHz) and MRI (14.1T), as shown in Figure 3. The ¹⁹F MRI results provide compelling evidence of a progressive increase in signal intensity as the pH transitions from neutral to more acidic conditions, effectively functioning as an 'on-off probe.' Additionally, our findings were corroborated by an in-cell ¹⁹F NMR experiment, which unveiled significant variations in T2 relaxation times both within and outside cells. This phenomenon is likely attributable to the acidic environment within lysosomes, offering valuable insights into the cellular microenvironment. Furthermore, preliminary data obtained from cancer cell lines extend the relevance of our probe, showcasing its sensitivity in detecting pH fluctuations. This potential carries significant promise for improving tumor imaging and advancing our understanding of cancer. Notably, the transition of cancer to a metastatic stage often corresponds with increased lysosomal activity, characterized by heightened lysosomal biogenesis and acidification. The ability of our probe to respond to such changes has substantial implications for cancer research and may pave the way for enhanced diagnostic and therapeutic strategies in the future.

Acknowledgements

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement No NOVA-MRI (859908). The authors acknowledge the funding from ERC‐2014‐StG‐336454‐CoNQUeST, TTW-NWO open technology grant STW-14716, ERC-2015-PoC-713524-CONQUEST, ERC-2019-PoC-862989-CENYA, and ERA-CVD JTC2017-044.