Abstract
Fluorine-19 (19F) Magnetic Resonance Imaging (MRI) is an emerging modality for molecular imaging and cell tracking. The hydrophobicity of current exogenous probes, perfluorocarbons (PFCs) and perfluoropolyethers (PFPEs), limits the formulation options available for in vivo applications. Hydrophilic probes permit more formulation flexibility. Further, the broad Nuclear Magnetic Resonance (NMR) chemical shift range of organofluorine species enables multiple probes with unique 19F MR signatures for simultaneous interrogation of distinct molecular targets in vivo. We report herein a flexible approach to stable liposomal formulations of hydrophilic fluorinated molecules (each bearing numerous magnetically equivalent 19F atoms), with 19F encapsulation of up to 22.7 mg/mL and a per particle load of 3.6 × 106 19F atoms. Using a combination of such probes, we demonstrate, with no chemical shift artifacts, the simultaneous imaging of multiple targets within a given target volume by spectral 19F MRI.
Highlights
There has been a surge in interest in 19F Magnetic Resonance Imaging (MRI) as a molecular imaging and cell tracking modality, driven in part by advances in MR technology including improvement in radiofrequency (RF) coil design, the development of dual 19F/1H imaging, and advanced scan protocols[1]
Coupling of the respective hydrophilic and fluorinated moieties followed by deprotection to obtain the final compounds (Fig. 1b) all proceeded with excellent yields, and were optimized to generate gram quantities of each compound
19F MRI probes have the potential to simultaneously profile multiple molecular species/disease activity and disease sub-types within a target volume
Summary
There has been a surge in interest in 19F MRI as a molecular imaging and cell tracking modality, driven in part by advances in MR technology including improvement in radiofrequency (RF) coil design, the development of dual 19F/1H imaging, and advanced scan protocols[1]. These emulsions generally require the extensive use of surfactants, have limited shelf stability, low biocompatibility and degradability[6] Most of these molecules have magnetically diverse fluorine atoms resulting in chemical shift artifacts and diffuse 19F MR images[7]. Organofluorine molecules have a chemical shift range of >350 ppm[5] and a novel technique introduced by Goette et al.[8] showed that an excitation bandwidth of just 1–2 kHz is adequate to separately image complex 19F spin systems with high SNR These suggest a theoretical possibility of developing a series of as many as 30 organofluorine probes with unique MR signatures. As proof-of-concept, we designed, synthesized, and characterized four hydrophilic non-ionic fluorinated molecules ET0863, ET0876, ET0886, and ET090, each bearing magnetically equivalent 19F atoms These were formulated into stable liposomes and tested as a new class of contrast agents for spectral 19F MRI. We demonstrated, using in vitro phantoms as well as subcutaneous and intramuscular deposits of these formulations that they can be selectively imaged within a target volume even in the presence of the widely used inhalable fluorinated anesthetic, isoflurane, without any interference or chemical shift artifacts
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