Water-soluble fluorinated copolymers as highly sensitive ¹⁹F MRI tracers: From structure optimization to multimodal...

Fluorine magnetic resonance imaging (¹⁹F MRI) using polymer tracers overcomes limitations of conventional proton MRI by offering enhanced specificity. However, the lack of systematic comparisons among fluorinated polymers has hindered rational tracer design. In this study, we synthesized an extensive library of water-soluble fluorinated copolymers by varying ratios of hydrophilic and fluorinated monomers and evaluated their ¹⁹F MRI properties to identify key structure-property relationships. Optimizing the hydrophilicity of the non-fluorinated comonomer increased fluorine content without compromising water solubility, thereby enhancing the MRI signal. Factors such as chemical structure, molecular interactions, and magnetic relaxation times also significantly influenced tracer performance. The optimized copolymer, poly((N-(2,2,2-trifluoroethyl)acrylamide)₆₀-stat-(N-(2-hydroxyethyl)acrylamide)₄₀), exhibited unprecedented ¹⁹F MRI sensitivity with detection limits below 1 mg mL^-1, the highest reported to date. We demonstrated the tracer's potential through successful in vivo ¹⁹F MRI visualization of solid tumors in mouse models, highlighting its promise for advanced biomedical imaging applications.