Enhanced Performance of Polymeric ¹⁹F MRI Contrast Agents through Incorporation of Highly Water-Soluble Monomer MSEA

Abstract

19 F magnetic resonance imaging (MRI) is a powerful non-invasive imaging technique that shows tremendous potential for the diagnosis and monitoring of human diseases. Fluorinated compounds are commonly used as 19 F MRI contrast agents to develop "hot spot" imaging. To achieve high-resolution MR images, a high density of 19 F nuclei are required in the contrast agents. However, due to the inherent hydrophobicity of fluorinated moieties, aggregation of 19 F contrast agents with high fluorine content is often observed in aqueous solution, resulting in attenuated MR signal and low sensitivity, thus significantly limiting their further biological applications. Here we report the synthesis and characterization of a series of polymeric 19 F MRI contrast agents with high fluorine content by copolymerizing the well-known fluorinated monomer 2,2,2-trifluoroethyl acrylate (TFEA) with a highly water soluble monomer 2-(methylsulfinyl)ethyl acrylate (MSEA) using RAFT polymerization. We show that these polymeric contrast agents, although with high fluorine content, display remarkable imaging performance as evidenced by preferable relaxation properties and intense in vitro/vivo MRI signals, demonstrating the huge potential for eventual clinical applications such as MRI-guided disease diagnosis and therapy.

Partially Fluorinated Copolymers as Oxygen Sensitive 19F MRI Agents

“…FNMR was used to probe 19 Fr elaxation properties and peak widths at half-height (v 1/2 )o fa ll copolymers in aqueous solution.I maging agentsw ith al ong T 2 ,s hort T 1 ,a nd narrow v 1/2 that are ablet om aintain ah igh density of 19 Fn uclei demonstrate enhanced MRI sensitivity.U sing af ield strength of 11.7 Ta tacopolymer concentration of 20 mg mL À1 ,w eo bserved that 19 F T 1 values remained similar across each range of compositions containing the same fluorinated comonomer ( Figure 2). HexaFOEA copolymers displayed the lowest T 1 values ( % 350 ms), whichi sa lmost 100 ms and 200 ms lower than TFEA and NonaFOEA copolymers, respectively.T he T 1 and T 2 values of the TFEA copolymers are similar to the values previously reported at af ield strength of 9.4 T. [55] In agreement with previous reports, [35,36,43,44,46,56,66] we observed ad ecrease in 19 F T 2 with the addition of more fluorinated comonomers into the copolymer (Figure 2). This decrease has been ascribed to the segregation of a 19 F-rich phase within the solvated polymer in aqueous solution,a nd is responsible for attenuating 19 F T 2 values by restricting 19 Fm obility.W eo bserve higher T 2 values for HexaFOEA copolymerst han ap revious report utilizing a d-glucose glycol-comonomer at similar wt %f luorinated comonomer.…”

“…[65] For example, the highest performing reported TFEA copolymer achieves ac oncentration of 100 mm local [ 19 F] at ac opolymer concentration of 20 mg mL À1 . [55] The sensitivity of an imaging agent to pO 2 is directly related to its signal intensity;t herefore, no water soluble 19 FMRI agent has been developedf or the quantification of tissue pO 2 at clinically relevant fields trengths.…”

Main Chain Polysulfoxides as Active ‘Stealth’ Polymers with Additional Antioxidant and Anti-Inflammatory Behaviour

“…PMSEA was recently proposed again by Matyjaszewski with more modern syntheses based on Atom Transfer Radical Polymerization (ATRP) [29], electrochemically mediated ATRP (eATRP) [33], and surface-initiated ATRP [34]. PMSEA has often been shown to behave similarly to poly(PEG acrylate), with the possible advantage of a lower steric hindrance; for example, their block copolymers with fluorine-containing monomers have a comparable MRI performance (slightly more intense signals for PMSEA) [35], and cationic hyperbranched constructs have similar transfection efficiency (but better polyplex formation for PMSEA) [36].…”

“…PMSEA is also occasionally referred to as poly(DMSO) [35] due its dimethyl sulfoxide (DMSO)-like side chain (-CH 2 S(=O)CH 3 ). DMSO is indeed in itself one of the most benign/low toxicity organic solvents, being regularly used as a cryoprotective agent for cells and above all as a pharmaceutical excipient.…”

The effect of cationic groups on the stability of 19F MRI contrast agents in nanoparticles

“…In recent literature, two main strategies have been employed to incorporate fluorinated functionalities in a polymeric architecture, mainly due to the work of Whittaker and Thurecht. On the one hand, statistical copolymerization of a hydrophilic and a fluorine‐rich monomer results in a polymer with 19 F‐active side chains scattered throughout the main chain . On the other hand, functionalization of the end of the polymer chain with the use of a fluorinated chain‐transfer agent, has recently shown promising results …”