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Fluorous-Soluble Metal Chelate for Sensitive Fluorine-19 Magnetic Resonance Imaging Nanoemulsion Probes.
ACS Nano ( IF 17.1 ) Pub Date : 2018-12-07 , DOI: 10.1021/acsnano.8b04881
Amin Haghighat Jahromi 1 , Chao Wang 1 , Stephen R Adams 2 , Wenlian Zhu 1 , Kazim Narsinh 1, 3 , Hongyan Xu 1 , Danielle L Gray 4 , Roger Y Tsien 2, 5, 6 , Eric T Ahrens 1
Affiliation  

Fluorine-19 MRI is an emerging cellular imaging approach, enabling lucid, quantitative "hot-spot" imaging with no background signal. The utility of 19F-MRI to detect inflammation and cell therapy products in vivo could be expanded by improving the intrinsic sensitivity of the probe by molecular design. We describe a metal chelate based on a salicylidene-tris(aminomethyl)ethane core, with solubility in perfluorocarbon (PFC) oils, and a potent accelerator of the 19F longitudinal relaxation time ( T1). Shortening T1 can increase the 19F image sensitivity per time and decrease the minimum number of detectable cells. We used the condensation between the tripodal ligand tris-1,1,1-(aminomethyl)ethane and salicylaldehyde to form the salicylidene-tris(aminomethyl)ethane chelating agent (SALTAME). We purified four isomers of SALTAME, elucidated structures using X-ray scattering and NMR, and identified a single isomer with high PFC solubility. Mn4+, Fe3+, Co3+, and Ga3+ cations formed stable and separable chelates with SALTAME, but only Fe3+ yielded superior T1 shortening with modest line broadening at 3 and 9.4 T. We mixed Fe3+ chelate with perfluorooctyl bromide (PFOB) to formulate a stable paramagnetic nanoemulsion imaging probe and assessed its biocompatibility in macrophages in vitro using proliferation, cytotoxicity, and phenotypic cell assays. Signal-to-noise modeling of paramagnetic PFOB shows that sensitivity enhancement of nearly 4-fold is feasible at clinical magnetic field strengths using a 19F spin-density-weighted gradient-echo pulse sequence. We demonstrate the utility of this paramagnetic nanoemulsion as an in vivo MRI probe for detecting inflammation macrophages in mice. Overall, these paramagnetic PFC compounds represent a platform for the development of sensitive 19F probes.

中文翻译:

氟敏感金属螯合剂,用于灵敏的19氟磁共振成像纳米乳剂探针。

Fluorine-19 MRI是一种新兴的细胞成像方法,可在没有背景信号的情况下进行清晰,定量的“热点”成像。通过分子设计提高探针的固有灵敏度,可以扩展19F-MRI在体内检测炎症和细胞治疗产物的实用性。我们描述了基于水杨基-三(氨基甲基)乙烷核的金属螯合物,在全氟化碳(PFC)油中具有溶解性,以及19F纵向弛豫时间(T1)的有效促进剂。缩短T1可以提高每次19F图像的灵敏度,并减少可检测细胞的最小数量。我们使用三脚架配体tris-1,1,1-(氨基甲基)乙烷与水杨醛之间的缩合形成水杨基-三(氨基甲基)乙烷螯合剂(SALTAME)。我们纯化了SALTAME的四种异构体,使用X射线散射和NMR阐明了结构,并鉴定了具有高PFC溶解度的单一异构体。Mn4 +,Fe3 +,Co3 +和Ga3 +阳离子与SALTAME形成稳定且可分离的螯合物,但只有Fe3 +产生优异的T1缩短,在3和9.4 T时有适度的谱线展宽。我们将Fe3 +螯合物与全氟辛基溴化物(PFOB)混合在一起,从而制得稳定的顺磁性纳米乳液成像探针,并使用增殖,细胞毒性和表型细胞分析评估其在体外巨噬细胞中的生物相容性。顺磁性PFOB的信噪模型表明,使用19F自旋密度加权梯度回波脉冲序列,在临床磁场强度下将灵敏度提高近4倍是可行的。我们证明了这种顺磁性纳米乳剂作为体内MRI探针检测小鼠炎症巨噬细胞的效用。总体而言,这些顺磁性PFC化合物代表了开发敏感19F探针的平台。
更新日期:2018-12-07
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