Fluorine-Containing Block and Gradient Copoly(2-oxazoline)s Based on 2-(3,3,3-Trifluoropropyl)-2-oxazoline: A Quest for the Optimal Self-Assembled Structure for ¹⁹F Imaging

Abstract

The use of fluorinated contrast agents in magnetic resonance imaging (MRI) facilitates improved image quality due to the negligible amount of endogenous fluorine atoms in the body. In this work, we present a comprehensive study of the influence of the amphiphilic polymer structure and composition on its applicability as contrast agents in 19F MRI. Three series of novel fluorine-containing poly­(2-oxazoline) copolymers and terpolymers, hydrophilic–fluorophilic, hydrophilic–lipophilic–fluorophilic, and hydrophilic–thermoresponsive–fluorophilic, with block and gradient distributions of the fluorinated units, were synthesized. It was discovered that the CF3 in the 2-(3,3,3-trifluoropropyl)-2-oxazoline (CF3EtOx) group activated the cationic chain end, leading to faster copolymerization kinetics, whereby spontaneous monomer gradients were formed with accelerated incorporation of 2-methyl-2-oxazoline or 2-n-propyl-2-oxazoline with a gradual change to the less-nucleophilic CF3EtOx monomer. The obtained amphiphilic copolymers and terpolymers form spherical or wormlike micelles in water, which was confirmed using transmission electron microscopy (TEM), while small-angle X-ray scattering (SAXS) revealed the core–shell or core–double-shell morphologies of these nanoparticles. The core and shell sizes obey the scaling laws for starlike micelles predicted by the scaling theory. Biocompatibility studies confirm that all copolymers obtained are noncytotoxic and, at the same time, exhibit high sensitivity during in vitro 19F MRI studies. The gradient copolymers provide the best 19F MRI signal-to-noise ratio in comparison with the analogue block copolymer structures, making them most promising as 19F MRI contrast agents.

Straightforward Access to Block and Gradient Light‐Responsive Poly(2‐Oxazoline)S via Cationic Ring Opening Polymerization Of 2‐Azobenzenyl‐2‐Oxazoline

“…The block copolymers of the same composition could be prepared by subsequent polymerization of monomers. [28] However, the significant differences in the reactivity of the monomers allow the application of "One-Shot" copolymerization, when the more reactive comonomer (EtOx) could be polymerized in the presence of the second comonomer (AzBenOx) without its significant involvement in the polymerization reaction. [29,30] Thus, three block copolymers of different compositions were synthesized in two stages, as presented in Scheme 1.…”

Recent Research Progress of 19F Magnetic Resonance Imaging Probes: Principle, Design, and Their Application

“…Because of the superhydrophobicity of fluorine nuclei itself, introducing the hydrophilic species next to fluorine nuclei to enhance the hydration nearby the fluorine nuclei, which is the most commonly used strategy to promote the mobility of fluorine nuclei. The hydrophilic species include 2‐hydroxyethyl methacrylate, [ 70 ] N‐(2‐hydroxypropyl)methacrylamide, [ 71 ] zwitterionic monomer (carboxybetaine monomer), [ 74 ] glycidol, [ 75 ] 2‐methyl‐2‐oxazoline, [ 78,85 ] 2‐(methylsulfinyl) ethyl acrylate (MSEA), [ 79 ] glucose, [ 77 ] β ‐cyclodextrin, [ 81 ] PEG (OEG), [ 76 ] and so on.…”

Long-term in vivo dissolution of thermo- and pH-responsive, 19F magnetic resonance-traceable and injectable polymer implants

“…Additionally, as 19 F is the only naturally occurring isotope of uorine, no isotope enrichment is required. Another advantage is that 19 F tracers can be highly biocompatible and non-toxic [6][7][8][9][10][11][12][13] and have a broad range of chemical shis (−300 to 400 ppm), so multiple tracers can be simultaneously tracked with a higher sensitivity than other X-nuclei. Moreover, dual 1 H/ 19 F MR can be acquired using common scanners and radiofrequency coils with only minor hardware adjustments.…”