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

Abstract

19 F 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 19 F 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 19 F MRI contrast agents (CAs). The structural characteristics, conformation and aggregation behavior, 19 F NMR relaxation properties, and 19 F 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 19 F T 2 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 19 F T 2 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 19 F MRI CAs demonstrates that these polymers are an exciting new class of 19 F MRI CAs with extremely high fluorine content and outstanding imaging sensitivity.

Integrating Fluorinated Polymer and Manganese‐Layered Double Hydroxide Nanoparticles as pH‐activated 19F MRI Agents for Specific and Sensitive Detection of Breast Cancer

“…The formation of small aggregates in aqueous solution does not adversely influence the 19 F MR imaging performance even at high polymer concentrations (as evidenced by the long 19 F T 2 and intense 19 F NMR signal) in buffer solution with 10% fetal bovine serum (Table S1 and Figure S2, Supporting Information). Such observations are consistent with our previous studies . In this polymer, the fluorine content was ≈16.7 wt%, which is important for achieving high 19 F MR imaging sensitivity …”

“…Such observations are consistent with our previous studies . In this polymer, the fluorine content was ≈16.7 wt%, which is important for achieving high 19 F MR imaging sensitivity …”

Fluorinated PLGA Nanoparticles for Enhanced Drug Encapsulation and 19F NMR Detection

“…F 3 -PLGA NPs and F 9 -PLGA NPs showed T 1 values of 537 ms and 625 ms and T 2 values of 122 ms and 60 ms, respectively,i na greement with values found for other 19 FMRI active NP systems, [21] indicating their suitability for 19 FMRI applications. [22] As expected, the increase of 19 Fa toms in the molecular structure significantly raised the intensity of the 19 FNMR signal of F 9 -PLGA NPs with respectt ot hat of F 3 -PLGA NPs. This wasp rovedp erforming the 19 FNMR analysiso nF 3 -PLGA and F 9 -PLGA NP dispersions at the same polymerc oncentration in presenceo ft rifluoroacetic acid (TFA) standard solution ( Figure S2).…”

Partially Fluorinated Copolymers as Oxygen Sensitive 19F MRI Agents

“…PEGA homopolymers with a perfluoropolyether (PFPE) chain-end also demonstrate analogous behavior. [74] The application of poly(HexaFOEA-co-PEGA) andp oly(Nona-FOEA-co-PEGA) materials as sensitive 19 FM RI agents was validated by acquiring 19 FMRI images on a9 .4T Bruker small animal imaging system using a T 1 -weighted fast low angle shot (FLASH)p ulse sequence ( Figure 5). The highest performing HexaFOEA and NonaFOEA copolymers demonstrated two and three times higher sensitivity than TFEA copolymers, respectively.N onaFOEA andH exaFOEA copolymers demonstrate similarM RI SNR when incorporated at 30 and 40 mol %, despite NonaFOEA copolymers containing 1.5 times more fluorine content.W eh ypothesize this resultedf rom HexaFOEA copolymers having al ower T 1 than NonaFOEA copolymers.…”