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Emergent Fluorous Molecules and Their Uses in Molecular Imaging.

Authors :
Wang C
Adams SR
Ahrens ET
Source :
Accounts of chemical research [Acc Chem Res] 2021 Aug 03; Vol. 54 (15), pp. 3060-3070. Date of Electronic Publication: 2021 Jul 14.
Publication Year :
2021

Abstract

This Account summarizes recent advances in the chemistry of fluorocarbon nanoemulsion (FC NE) functionalization. We describe new families of fluorous molecules, such as chelators, fluorophores, and peptides, that are soluble in FC oils. These materials have helped transform the field of in vivo molecular imaging by enabling sensitive and cell-specific imaging using magnetic resonance imaging (MRI), positron emission tomography (PET), and fluorescence detection. FC emulsions, historically considered for artificial blood substitutes, are routinely used for ultrasound imaging in clinic and have a proven safety profile and a well-characterized biodistribution and pharmacokinetics. The inertness of fluorocarbons contributes to their low toxicity but makes functionalization difficult. The high electronegativity of fluorine imparts very low cohesive energy density and Lewis basicity to heavily fluorinated compounds, making dissolution of metal ions and organic molecules challenging. Functionalization is further complicated by colloidal instability toward heat and pH, as well as limited availability of biocompatible surfactants.We have devised new fluorous chelators that overcome solubility barriers and are able to bind a range of metal ions with high thermodynamic stability and biocompatibility. NE harboring chelators in the fluorous phase are a powerful platform for the development of multimodal imaging agents. These compositions rapidly capture metal ions added to the aqueous phase, thereby functionalizing NEs in useful ways. For example, Fe <superscript>3+</superscript> encapsulation imparts a strong paramagnetic relaxation effect on <superscript>19</superscript> F T <subscript>1</subscript> that dramatically accelerates <superscript>19</superscript> F MRI data acquisition times and hence sensitivity in cell tracking applications. Alternatively, <superscript>89</superscript> Zr encapsulation creates a sensitive and versatile PET probe for inflammatory macrophage detection. Adding lanthanides, such as Eu <superscript>3+</superscript> , renders NE luminescent. Beyond chelators, this Account further covers our progress in formulating NEs with fluorophores, such as cyanine or BODIPY dyes, with their utility demonstrated in fluorescence imaging, biosensing, flow cytometry and histology. Fluorous dyes soluble in FC oils are also key enablers for nascent whole-body imaging technologies such as cryo-fluorescence tomography (CFT). Additionally, fluorous cell-penetrating peptides inserted on the NE surface increase the uptake of NE by ∼8-fold in weakly phagocytic stem cells and lymphocytes used in immunotherapy, resulting in significant leaps in detection sensitivity in vivo.

Details

Language :
English
ISSN :
1520-4898
Volume :
54
Issue :
15
Database :
MEDLINE
Journal :
Accounts of chemical research
Publication Type :
Academic Journal
Accession number :
34259521
Full Text :
https://doi.org/10.1021/acs.accounts.1c00278