Journal
ACS NANO
Volume 13, Issue 1, Pages 143-151Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.8b04881
Keywords
MRI; F-19; metal chelate; perfluorocarbon; nanoemulsion; macrophage; inflammation
Categories
Funding
- National Institutes of Health (NIH) [R01-EB017271, R01-EB024015, R01 CA139579]
- California Institute for Regenerative Medicine [LA1-C12-06919]
- Cook Medical Cesare Gianturco/RSNA Research Resident grant
- NIH [T32 4T32EB005970]
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Fluorine-19 MRI is an emerging cellular imaging approach, enabling lucid, quantitative hot-spot imaging with no background signal. The utility of F-19-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 F-19 longitudinal relaxation time (T-1). Shortening T-1 can increase the F-19 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 T-1 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 F-19 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 F-19 probes.
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