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

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PFPE-Based Polymeric 19F MRI Agents: A New Class of Contrast Agents with Outstanding Sensitivity
Macromolecules ( IF 5.1 ) Pub Date : 2017-07-25 00:00:00 , DOI: 10.1021/acs.macromol.7b01285
Cheng Zhang _{1,

2} , Shehzahdi Shebbrin Moonshi _{1,

2} , Yanxiao Han , Simon Puttick _{1,

2} , Hui Peng _{1,

2} , Bryan John Abel Magoling ₁ , James C. Reid ₁ , Stefano Bernardi ₁ , Debra J. Searles _{1,

3} , Petr Král ₄ , Andrew K. Whittaker _{1,

2}

Affiliation

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.

中文翻译：

基于PFPE的聚合物¹⁹ F MRI剂：具有出色灵敏度的新型造影剂

¹⁹ F磁共振成像（MRI）是一种功能强大的非侵入性成像技术，已被证明具有检测重要疾病的潜力。¹⁹ F MRI试剂设计中的主要挑战是信号衰减，这是由于具有大量氟原子的探针的溶解度和分段迁移率降低所致。需要仔细选择氟化部分，以在高成像灵敏度所需的氟含量下保持图像质量。在这里，我们报告的低聚（乙二醇）甲基醚丙烯酸酯（poly（OEGA）_m -PFPE）的全氟聚醚（PFPE）端官能化均聚物的合成作为高灵敏度¹⁹ F MRI造影剂（CAs）。结构特征，构象和聚集行为，^{详细研究了19} F NMR弛豫特性和¹⁹ F MR成像。动态光散射和分子动力学（MD）模拟进行了，并证明了聚（OEGA）_米-PFPE具有最长聚（OEGA）_米段（米= 20）的水，而聚（OEGA）经历单链折叠₁₀ -具有较短OEGA链段的PFPE和聚（OEGA）₄ -PFPE经历多链聚集。在PBS中和存在血清（> 80 ms）的情况下，对所有聚（OEGA）_m -PFPE聚合物测量了长的¹⁹ F T ₂弛豫时间，而¹⁹ F T却没有明显降低随着氟含量增加至约30wt％，观察到图₂。此外，信噪比随氟浓度的增加而线性增加，表明基于PFPE的聚合物可以用作定量示踪剂。此外，我们研究了具有不同聚集特性的聚合物的体内行为，特别是它们的生物分布。通过控制疏水性和亲水性之间的平衡，可以控制聚集状态，从而在鼠模型中导致不同的循环行为。这种聚合PFPE基合成的第一次报告^19点˚FMRI的CA表明，这些聚合物是一个令人兴奋的新一类¹⁹具有极高氟含量和出色成像灵敏度的F MRICA。

更新日期：2017-07-25

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