PFPE-Based Polymeric ¹⁹F MRI Agents: A New Class of Contrast Agents with Outstanding Sensitivity

¹⁹F magnetic resonance imaging (MRI) is a powerful noninvasive imaging technique with demonstrated potential for the detection of important diseases. The major challenge in the design of ¹⁹F MRI agents is signal attenuation caused by the reduced solubility and segmental mobility of probes with high numbers of fluorine atoms. Careful choice of the fluorinated moiety is required to maintain image quality at the fluorine contents required for high imaging sensitivity. Here we report the synthesis of perfluoropolyether (PFPE) end-functionalized homopolymers of oligo­(ethylene glycol) methyl ether acrylate (poly­(OEGA)_m-PFPE) as highly sensitive ¹⁹F MRI contrast agents (CAs). The structural characteristics, conformation and aggregation behavior, ¹⁹F NMR relaxation properties, and ¹⁹F MR imaging were studied in detail. Dynamic light scattering and molecular dynamics (MD) simulations were conducted and demonstrated that poly­(OEGA)_m-PFPE with the longest poly­(OEGA)_m segments (m = 20) undergoes single-chain folding in water while poly­(OEGA)₁₀-PFPE and poly­(OEGA)₄-PFPE with shorter OEGA segments experience multiple-chain aggregation. Long ¹⁹F T₂ relaxation times were measured for all poly­(OEGA)_m-PFPE polymers in PBS and in the presence of serum (>80 ms), and no obvious decrease in ¹⁹F T₂ was observed with increasing fluorine content up to ∼30 wt %. Moreover, the signal-to-noise ratio increased linearly with increasing concentration of fluorine, indicating that the PFPE-based polymers can be applied as quantitative tracers. Furthermore, we investigated the in vivo behavior, in particular their biodistribution, of the polymers with different aggregation properties. Control over the balance of hydrophobicity and hydrophilicity allows manipulation of the aggregation state, and this leads to different circulation behavior in a murine model. This first report of the synthesis of polymeric PFPE-based ¹⁹F MRI CAs demonstrates that these polymers are an exciting new class of ¹⁹F MRI CAs with extremely high fluorine content and outstanding imaging sensitivity.