Fluorous-Soluble Metal Chelate for Sensitive Fluorine-19 Magnetic Resonance Imaging Nanoemulsion Probes

Abstract

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.

The sensitivity of magnetic particle imaging and fluorine-19 magnetic resonance imaging for cell tracking

“…It is expected that SPION surface modifications will be improve labeling efficiency without transfection agents 8 , 28 . Further improvements to PFPE nanoemulsions will enhance 19 F cellular sensitivity, such as incorporation of paramagnetic agents 29 , 30 , or the addition of surface modifications to enhance the uptake of PFPE nanoemulsions 31 .…”

Combination of bioresponsive chelates and perfluorinated lipid nanoparticles enables in vivo MRI probe quantification

“…[11][12][13] In attempts to improve the performances of PFC-based CAs, nanosized systems have been designed, combining PFC cores and paramagnetic ions such as Gd(III) and Fe(III). [14][15][16] In such systems, the paramagnetic relaxation enhancement (PRE) effect of the paramagnetic ions does not result in a responsive behaviour for the probe, but usually decreases the relaxation times of the 19 F nuclei, allowing for faster acquisitions. Furthermore, nanoparticles have proved as an advantageous tool in the design of nanosized responsive platforms for molecular imaging application.…”

The sensitivity of magnetic particle imaging and fluorine-19 magnetic resonance imaging for cell tracking

“…19 F may not be suitable for tracking labeled cancer cells to metastatic sites. Further improvements to PFPE nanoemulsions will enhance 19 F cellular sensitivity, such as incorporation of paramagnetic agents 16,17 , or the addition of surface modifications to enhance the uptake of PFPE nanoemulsions 18 .…”