Stimuli-Responsive Partially Fluorinated Polymers as ¹⁹F Switchable Magnetic Resonance Imaging Tracers

Abstract

Fluorine magnetic resonance imaging (¹⁹F MRI) has emerged as a promising imaging technique. Unlike conventional ¹H MRI, there is no detectable endogenous background signal in soft tissue. Perfluorocarbon (PFCs) nanoemulsions, with a high number of equivalent fluorine atoms, are perhaps the most common reported examples for ¹⁹F MRI applications. Nevertheless, the large size and inadequate emulsion stability limit their efficiency. This review provides a comprehensive overview of partially fluorinated polymers as a promising new class of ¹⁹F MRI tracers, offering an attractive alternative to traditional perfluorocarbon-based systems. It examines how polymer composition, fluorine content, and macromolecular architecture play critical roles in regulating relaxation properties and signal intensity. Special consideration is given to recent advancements in stimuli-responsive fluorinated polymers, which can undergo conformational transition in response to specific stimuli (e.g., pH, redox, or temperature). These confirmational transitions can result in “switchable” ¹⁹F MRI signals, which hold significant potential for targeted imaging and early disease diagnosis, particularly in cancer and inflammatory disorders.

1. Introduction

Since its development by Lauterbur in the early 1970s, ¹H magnetic resonance imaging (MRI) has been recognized as the most powerful and versatile noninvasive imaging technique for visually distinguishing between background tissue and regions of diagnostic interest. MRI has several advantages, including its capability to produce 3D images with relatively high temporal and spatial resolution. In contrast to X-ray computed tomography (CT), MRI does not involve the use of any ionizing radiation. Furthermore, unlike radionuclide-based techniques (e.g., positron emission tomography (PET) and single-photon emission computed tomography (SPECT)), MRI does not require the use of radioactive tracers. Moreover, MRI has no limitations due to penetration depth often seen in optical imaging (e.g., fluorescence). Nevertheless, contrast agents are usually required to highlight specific tissues of diagnostic interest. −

¹H MRI contrast agents can be classified into two main classes, depending on whether they cause a change in spin–lattice relaxation time T ₁, , or spin–spin relaxation time T ₂. − T ₁ contrast agents, such as paramagnetic gadolinium ion complexes, often shorten the T ₁ relaxation time of neighboring water protons, so the enhanced parts appear brighter on T ₁-weighted images (positive contrast). In contrast, T ₂ contrast agents significantly shorten the T ₂ relaxation time. Consequently, the enhanced region appears darker on T ₂-weighted images (negative contrast), with iron oxide nanoparticles being the most extensively reported examples. Despite the contrast generated within MR images, large background signals arising from water protons in the adjacent living tissues often result in subtle contrast for both classes, accompanied by imaging artifacts. Moreover, quantitative applications of these ¹H MRI contrast agents are limited, as they are, in principle, detected indirectly by altering the relaxation times of nearby water protons. More importantly, safety concerns are associated with the use of such metal-based contrast agents. The US Food and Drug Administration (FDA) is requiring changes in the use of gadolinium-based contrast agents to minimize the risk of nephrogenic systemic fibrosis and kidney dysfunction. ,

Recently, the use of non-¹H nuclei with high MR receptivity (e.g., ¹³C, ²³Na, ³¹P, ¹⁹F), which MRI can image to generate distinct ‘hotspot’ signals, has gained considerable attention as an alternative to conventional ¹H MRI. Among these, the ¹⁹F nucleus is particularly attractive due to its favorable NMR properties, including 100% natural abundance, a large gyromagnetic ratio (40.08 compared with 42.58 MHz T^–1 of ¹H), and high sensitivity (83% relative to ¹H). Furthermore, ¹⁹F MRI has endogenous background-free signals, with only a trace concentration (<10^–6 M) of fluorine found in the body in the form of immobilized salts, primarily in bones and teeth, resulting in a very short T ₂ relaxation time that is not visible to conventional MRI.

¹⁹F MRI was first demonstrated by Holland et al. in 1977, only a few years after the establishment of ¹H MRI by Lauterbur. However, the first in vivo ¹⁹F MRI images were not reported until 1985 by McFarland et al., who described images of rats using fluorinated probes. Since then, there has been remarkable progress in ¹⁹F MRI for numerous quantitative applications, including real-time monitoring of drug delivery, tumor oxygenation studies, and cell tracking. − Fluorinated tracers ranging from small perfluorocarbon compounds (PFCs) (e.g., perfluoro-15-crown-5-ether (PFCE)) to linear perfluoropolyether (PFPE) with a high number of equivalent fluorine atoms to maximize the signal-to-noise ratio and provide a single ¹⁹F resonance signal have been widely investigated. − Formulations of these PFCs into oil/water nanoemulsion droplets with diameters of several hundred nanometers, using different Pluronic surfactants, have been the most widely used approach to overcome their poor solubility for in vivo applications. − The US FDA has approved several PFC formulations for use in various clinical trials. They are commercially available under the names Cell Sense and V-Sense (Celsense, Inc., Pittsburgh, USA) for PFPE and PFCE nanoemulsion formulations, respectively. Nevertheless, the large size (∼200 nm) and known instability of such nanoemulsion formulations limit their use, particularly for imaging small features. The use of PFCs as ¹⁹F MRI tracers in biological applications is beyond the scope of this review and has been covered in many reviews. ,,, The scope of this review is to cover the development of more sophisticated partially fluorinated polymers as ¹⁹F MRI tracers.

2. Partially Fluorinated Polymers

Over the past few decades, extensive attention has been devoted to the development of partially fluorinated polymers as potential new generations of ¹⁹F MRI tracers, owing to the versatility of polymer architectures, compositions, and end-group functionalities. − Representative vinyl monomers used in the synthesis of such fluorinated polymers are illustrated in Figure . To achieve a good MRI signal, partially fluorinated polymers should meet specific criteria, including high fluorine content, long T ₂ relaxation times, and short T ₁ relaxation times, as clearly stated in eq .

$$I=N(F)\left[1-2\exp \left(\frac{-(T_{\mathrm{R}}-T_{\mathrm{E}}/2}{T_1}\right)+\exp \left(\frac{{-T}_{\mathrm{R}}}{T_1}\right)]\exp \left(\frac{{-T}_{\mathrm{E}}}{T_2}\right)\right]$$ 1

Where I is the imaging intensity, N(F) is ¹⁹F content in the volume element of the image, and T _R and T _E are the pulse sequence repetition time and echo delay times, respectively. Furthermore, a fluorinated polymer should preferably have a single fluorine signal, as multiple fluorine signals may result in lower signal intensity and imaging artifacts.

1.

Representative vinyl monomers discussed in this review for the synthesis of partially fluorinated polymers designed for ¹⁹F MRI applications. Red-circled structures highlight hydrophilic monomers.

Generally, fluorinated polymers in solution tend to exhibit efficient T ₁ relaxation times (i.e., short T ₁). A short T ₁ relaxation time is favorable as it determines the relaxation delay between pulses. , The relaxation delay between scans should be at least five times the longest T ₁ relaxation time to ensure that the nuclear spin system relaxes back to its equilibrium before the next pulse is applied. A short T ₁ relaxation time allows more scans within a certain time frame and hence, a better signal-to-noise ratio can be acquired. Nonetheless, due to the slow macromolecular motion, partially fluorinated polymers also tend to have short T ₂ relaxation times. Since the signal line-width is inversely proportional to the T ₂ relaxation time, a short T ₂ results in signal line-broadening, and in some cases, it might lead to a loss of signal intensity.

3. Designing Partially Fluorinated Polymers

3.1. Polymeric Micelles

The relative motion of ¹⁹F nuclei, and hence the T ₂ relaxation times, is significantly influenced by polymer structure and composition. Recently, several micelles with poorly solvated cores and water-soluble coronas have been developed as ¹⁹F MRI tracers. − Generally, fluorine nuclei within chain segments undergoing restricted motion exhibit short T ₂ relaxation times, , whereas fluorine nuclei within water-soluble corona experiencing large amplitude molecular motion show reasonably long T ₂ relaxation times. , Polymeric micelles incorporating hydrophobic fluorinated comonomers often exhibit shortened T ₂ relaxation times, as the fluorinated units tend to solidify within the poorly solvated hydrophobic core. For example, Nyström et al. synthesized linear poly­(acrylic acid)-b-poly­(styrene-co-pentafluorostyrene) PAA-b-(PS-co-PPFS) block copolymers that self-assembled into micelles in aqueous solution. In this study, ¹⁹F nuclei were incorporated within the poorly solvated hydrophobic core, resulting in a nondetectable ¹⁹F signal from the aqueous solution. Similarly, Peng et al. developed a range of amphiphilic block copolymers in which poly­(acrylic acid) represents the hydrophilic region and n-butyl acrylate copolymerized with either trifluoroethyl acrylate (TFEA) or trifluoroethyl methacrylate (TFEMA) represents the hydrophobic region, as illustrated in Figure a. Such block copolymers also self-assembled into micelles in aqueous solution with the ¹⁹F nuclei incorporated within the hydrophobic cores. However, in this case, due to the low glass transition temperature (T _g) of the core components (i.e., acrylate monomers), the ¹⁹F signal was detectable, with a low T ₂ value of 1.75 ms and a reasonable T ₁ value of ∼500 ms (7 T).

2.

(a) Amphiphilic copolymers of PAA-b-P­(nBA-co-TFE­(M))­A, with fluorinated segment confined within hydrophobic core used as ¹⁹F MRI tracers, resulted in poor ¹⁹F MRI performance. Adapted with permission from ref . Copyright 2009 American Chemical Society. (b) Amphiphilic hyperbranched fluoropolymers with fluorinated segments within the hydrated shell resulted in enhanced ¹⁹F MRI performance. Adapted with permission from ref . Copyright 2008 American Chemical Society.

Incorporating a small amount of hydrophilic monomer within the poorly solvated fluorinated hydrophobic core can significantly enhance ¹⁹F MRI performance. For example, Panakkal et al. reported the synthesis of fluorinated nanoparticles via aqueous polymerization-induced self-assembly (PISA) of TFEA using a polyethylene glycol (PEG)-based macro chain transfer agent (macro-CTA). As expected, the tight packing of the fluorinated hydrophobic core resulted in a negligible ¹⁹F NMR signal and poor relaxation properties. Their attempts to increase the hydrophilicity of the fluorinated core by incorporating different amounts of N-hydroxyethyl acrylamide (HEAM), ranging from 10 to 30 mol %, resulted in a significant increase in the T ₂ value from 12.2 to 40.5 ms, with no significant change in the T ₁ relaxation time of 500 (4.7 T). This, in turn, resulted in overall substantial enhancement of ¹⁹F MRI imaging performance.

The amphiphilic gradient copolymer-derived nanoparticles with a fluorinated core, formed by statistical copolymerization, often have a softer and less compact core and hence better ¹⁹F MRI signal intensity compared to their block analogues. For example, Panakkal et al. reported the use of statistical or block polymerization-induced self-assembly (PISA) of hydrophilic poly­(ethylene glycol) methyl ether methacrylate (PEGMA) with core-forming N,N-(2,2,2-trifluoroethyl)­acrylamide (TFEAM) for the synthesis of gradient and block amphiphilic copolymer nanoparticles, respectively. Although both fluorinated nanoparticles tracers were successfully visualized in vitro, the gradient copolymer tracers had significantly greater ¹⁹F MRI intensities with better T ₁ and T ₂ values (T ₁ = 300 ms, T ₂ > 50, 1.5 T) than their block copolymer analogues at the same polymer concentration (T ₂ = 450 ms, T ₂ < 40, 1.5 T). The enhanced ¹⁹F MRI performance of gradient nanoparticles can be ascribed to the presence of the hydrophilic monomer within the fluorinated core, which led to plasticization and extended T ₂ relaxation times (Figure ). Insufficient incorporation of a hydrophilic comonomer can result in the fluorinated core being too tightly packed, leading to severely shortened T ₂ values and limited MRI sensitivity despite a high fluorine content. For example, Wallat et al. reported the synthesis and ¹⁹F MRI evaluation of low-molecular-weight fluorinated amphiphilic copolymers that self-assemble into micelles. The statically random copolymer was synthesized via atom transfer radical polymerization (ATRP) of TFEMA and oligo­(ethylene glycol) methyl ether methacrylate (OEGMEMA) using an azide-terminated initiator. The amphiphilic copolymer self-assembled in aqueous solution into micelles with fluorinated units sequestered into a poorly solvated core and OEGMEMA segments, as verified by ¹⁹F NMR in D₂O. Although the statistical architecture maximized fluorine loading, the confinement of fluorinated segments within the core resulted in a reasonable T ₁ value of 380 ms but a low T ₂ value of 2 ms (9.2 T), attributed to the confinement of fluorinated segments in the micelle core. Detectable ¹⁹F MRI phantom images of the copolymers were obtained at concentrations as low as 2.1 mM.

3.

(a) Statistical PISA copolymerization of PEGMA and TFEAM resulted in gradient copolymers with (b) enhanced ¹⁹F MRI performance in comparison with their block copolymer analogues. Adapted with permission from ref . Copyright 2024 American Chemical Society.

In contrast, the incorporation of fluorine nuclei within the water-soluble shell enhances their motion, resulting in elongation of T ₂ relaxation times and improved image intensity. Wooley et al. reported a series of amphiphilic star fluoropolymers with hydrophobic hyperbranched core previously synthesized via SCVP mediated by ATRP, and grafted poly­(acrylic acid-co-trifluoroethyl methacrylate) P­(AA-co-TFEMA) copolymer shell (Figure b). , Such amphiphilic block copolymers were successfully self-assembled into stable micelles in aqueous solution. In this study, fluorine nuclei were incorporated within the water-soluble shell, resulting in a reasonably short T ₁ of ∼500 ms and a long T ₂ (50–56 ms) at 11.75 T. Although such micelles successfully produced adequate MRI images, due to the limited fluorine concentrations, a long scan time was required, and therefore, they were not suitable for in vivo application.

Another example was reported by Zhao et al., who reported the synthesis of a library of fluorinated diblock copolymer of poly­(oligo­(ethylene glycol) methyl ether methacrylate-co-2,2,2-trifluoroethyl acrylate-b-poly­(styrene-co-3-vinylbenzaldehyde) P­(OEGA-co-TFEA)-b-P­(St-co-VBA)) nanoparticles, including spheres, worms, and vesicles, via RAFT-mediated PISA. The fluorinated monomers were located within the solvated shell, resulting in short T ₁ values of about 537 ms and reasonable T ₂ relaxation times of 176 ms (9.4 T) for all nanoparticles, regardless of their morphology, suggesting similar dynamics of the fluorinated shell for the different morphologies. ¹⁹F MRI signal intensity, though, was strongly dependent on the morphology, as the surface area, and hence the fluorine content, changes. The intensity of the ¹⁹F MRI signal increased with increasing fluorine content from spherical particles to vesicles.

3.2. Branched Polymers

As mentioned earlier, a high ¹⁹F concentration is required to achieve a good signal-to-noise ratio. However, due to the inherent hydrophobicity of fluorinated moieties, high fluorine concentrations often cause aggregation in aqueous solution, leading to shortened T ₂ relaxation times and attenuated MRI signal. It is essential to tailor the structure to load a high concentration of ¹⁹F while maintaining segment motion. Among various polymeric architectures, branched polymers are especially promising due to their constrained shape that minimizes fluorine dipole–dipole interactions by maximizing the distance between the spins (fluorine and protons). , Furthermore, high ¹⁹F contents can be achieved (up to 20 mol % fluorinated monomer) while maintaining decent water solubility (Figure a). For example, Thurecht et al. reported a series of fluorinated TFEA hyperbranched polymers with acid, alkyne, and mannose end-groups synthesized via RAFT polymerization in the presence of ethylene glycol dimethacrylate as a branching agent, which was then chain extended with polyethylene glycol monomethyl ether methacrylate. Hyperbranched polymers with acid functionalities exhibited a short T ₁ of about 500 ms and a relatively long T ₂ of 88 ms at 16.4 T. These hyperbranched polymers were successfully imaged in vivo using ¹⁹F MRI in under 10 min. While a branched structure is favorable to minimize fluorine dipole–dipole interaction, increasing the degree of branching (DB) might lead to a decrease in T ₂ relaxation times due to an increase in compactness and rigidity. For example, Wang et al. reported the synthesis of a series of segmented highly branched polymers (SHBPs) comprising fluoro- and PEG-based monomers by SCVP mediated by RAFT. Library of SHBPs with different compositions and DB were prepared by varying the monomer type (TFEA vs TFEMA) and feed ratio of monomer to chain transfer monomer (CTM). ¹⁹F NMR properties were strongly influenced by monomer composition. The study concluded that increasing the DB of SHBPs led to a decrease in T ₂ relaxation times due to an increase in compactness, rigidity, and restricted segmental motion. Hence, the DB and fluorine contents should be finely tuned to obtain a reasonable signal-to-noise ratio. Furthermore, SHBPs composed of lower T _g monomer (i.e., TFEA) had much longer T ₂ relaxation times in comparison with their methacrylate analogues, since fluorine atoms in acrylate backbones are more mobile.

4.

(a) Partially fluorinated hydrophilic branched copolymers, (b) statistical copolymer of fluorinated monomers with highly hydrophilic monomer, (c) homopolymer of hydrophilic fluorinated monomers can achieve high monomer contents with good water solubility and hence enhanced ¹⁹F MRI signal intensity.

3.3. Linear Polymers

More recently, a keen interest has been devoted to the development of highly water-soluble linear fluorinated polymers with high fluorine contents. A high content of fluorine, while maintaining water solubility of the fluorinated segments within polymers, is required for adequate ¹⁹F MRI performance. This can be achieved by either the statistical copolymerization of fluorinated monomers with highly hydrophilic monomers , or the homopolymerization of hydrophilic fluorinated monomers (Figure ). −

Statistical copolymerization of a fluorinated monomer with a highly hydrophilic monomer has been recently found to improve relaxation properties and imaging performance. For example, Fu et al. reported the synthesis and characterization of a series of polymeric ¹⁹F MRI tracers with high fluorine content by copolymerizing TFEA as fluorinated monomer with a highly water-soluble monomer 2-(methylsulfinyl)­ethyl acrylate (MSEA). The tracers with high fluorine content (5.8–19.3 wt %) showed remarkable T ₂ relaxation times of 22–330 ms (T ₁ = 444–641 ms, 9.4 T) and an intense ¹⁹F MRI signal. Recently, Sedlacek et al. reported the synthesis of a series of statistical fluorinated water-soluble poly­(2-oxazoline)­s (PAOx) via controlled side-chain hydrolysis of poly­(2- methyl-2-oxazoline) followed by reacylation of its ethylenimine moieties by difluoroacetic anhydride. The composition of fluorinated (PAOx) was optimized for maximal ¹⁹F MRI properties, while maintaining good water solubility. Copolymers with up to 13 wt % fluorine contents remained water-soluble with very decent relaxation times (T ₂ = 161–115 ms, T ₁ ∼ 300, 4.7 T). This was demonstrated by its outstanding MRI performance, both in vitro and in vivo. More recently, the same group reported the synthesis of a library of water-soluble statistical fluorinated copolymers based on substituted TFEA and TFEAM co/monomers to evaluate how varying the monomer composition and ratio can affect ¹⁹F MRI properties. Due to their good water solubility, partially fluorinated polyacrylamide achieved significantly higher fluorine contents (of up to 25 wt %) with much better ¹⁹F MRI performance compared to their polyacrylate analogues. Furthermore, among numerous hydrophilic acrylamide monomers copolymerized with TFEAM (Figure ), hydroxylated monomers (HEAM, DHPAM, and THAM in Figure ) exhibited better water solubility with high fluorinated contents and enhanced ¹⁹F MRI signal intensity.

5.

(a) Statistical copolymerization of TFEAM with various hydrophilic acrylamide comonomers. (b) ¹⁹F NMR SNR as a function of fluorine contents, (c) ¹H MRI and ¹⁹F MRI phantom images, (d) ¹⁹F NMR and ¹⁹F MRS of fluorinated copolymers. Adapted with permission from ref . Copyright 2025, Elsevier.

The synthesis of hydrophilic fluorinated homopolymer with high fluorine contents (up to 25 wt %) has recently been reported for optimal ¹⁹F MRI sensitivity. Fu et al. reported a new class of water-soluble homofluoropolymers with a sulfoxide side chain structure, synthesized via RAFT polymerization of N-(2-((2,2,2-trifluoroethyl)­sulfinyl)­ethyl)­acrylamide (FSAM). Despite its high fluorine content of up to 25 wt %, fluoropolymers exhibit high water solubility, with outstanding ¹⁹F MRI T ₂ relaxation times of 430 ms at 7.4 T for a polymer with a number-average molecular weight (M _n) of 10 kDa, and an intense ¹⁹F MRI signal. The high molecular weight polymer showed lower T ₂ relaxation times of 370 ms, but similar MRI detection limits, which is perhaps due to high fluorine content. Similarly, Feng et al. reported the synthesis of a series of hydrophilic carboxybetaine zwitterionic fluorinated homopolymers. The polymer remained soluble in water and overcame the hydrophobic aggregation-induced signal attenuation despite the high fluorine contents (19.1 wt %) of the zwitterionic fluorinated homopolymer poly­(N-(2-(methacryloyloxy) ethyl)-N-methyl-N-(3, 3, 3-trifluoropropyl)-glycine) (CBF3). The polymer exhibited a reasonable T ₂ relaxation time of approximately 55 ms, regardless of the degree of polymerization (DP) (range from 10 to 200), with an intense ¹⁹F MRI signal.

4. ¹⁹F MRI Stimuli-Responsive Tracers

More recently, there has been a keen interest in the design of ¹⁹F MRI stimuli-responsive tracers for cancer diagnostics, offering high specificity and sensitivity through environment-triggered signal activation. ,− Unlike conventional tracers, ¹⁹F MRI stimuli-responsive tracers remain “invisible” under normal physiological conditions and are selectively “switched on” in the tumor microenvironment, which is often characterized by acidic pH, elevated levels of reactive oxygen species (ROS), redox imbalances, or enzyme overexpression. By integrating responsive monomers (Figure ) into partially fluorinated polymeric structures, these agents enable targeted imaging of cancerous tissues with minimal background interference. ¹⁹F MRI signal intensity switch is often achieved due to changes in mobility of fluorinated segments within polymer chains. The signal intensity switch primarily relies on four main mechanisms: assembly disassembly transition, deswelling-swelling transition, transformation from high molecular weight polymers to low molecular weight polymer, or the release of fluorinated moieties (Figure ). Non-cross-linked polymeric micelles often undergo assembly disassembly transition, whereas cross-linked polymeric micelles often undergo deswelling-swelling transition upon enhancing water solubility of responsive monomers. Both transitions result in a significant increase in ¹⁹F MRI signal intensity. Cleavage of the cleavable linkage results in the transformation from high molecular weight polymers to either low molecular weight polymers or fluorinated end groups. Transformation into low molecular fluorinated polymers or small compounds significantly enhances T ₂ relaxation times due to their higher mobility, resulting in an intense ¹⁹F MRI signal. A summary of 19F MRI switchable tracers discussed in this review is found in Table .

6.

Stimuli-responsive vinyl monomers covered in this review.

7.

Schematic illustration of the main mechanisms of stimuli-responsive ¹⁹F MRI tracers discussed in this review.

1. Summary of ¹⁹MRI Switchable Tracers Reported in This Review .

19F MRI tracer	morphology/architecture	response	mechanism	refs
PEG-b-P( DEAMA- co-TFEMA)	cross-linked micelles (nanogel)	pH	deswelling-swelling
PPEGMA-b-P(TFEA-co-DMAEMA)	star polymer	pH	deswelling-swelling
PPEGMA-b-P(TFEMA-co-DMAEMA)	star with cross-linked core	pH	deswelling-swelling
PEO-b-P(DPA-co-TFE)	micelles	pH	assembly-disassembly
PTFEMA-b-P(TFEMA-co-DMAEMA)	micelles	pH	assembly-disassembly
PEG-b-P(TFEMA-co-ETEMA)	micelles	ROS	assembly-disassembly
PEG-b-PFTAM	micelles	ROS	assembly-disassembly
PPEGMA-b-P(AMA-DNBS-F)	micelles	reduction	assembly-disassembly
P(HFEA-co-GlcA-co-BAC)	hyper-branched polymer	reduction	cleavage to low molecular weight polymer
PHPMA-b-PDFEA	micelles	temperature	no switchable signal
PMeOx-b-PDFEA	micelles	temperature	no switchable signal
PHPMA-b-P(DFEA-co-FcCFA)	micelles	temperature and ROS	assembly-disassembly
PHPMA-b-P(DFEA-co-ImPAM)	micelles	temperature and pH	assembly-disassembly

^aResponsive moieties are in bold.

4.1. pH-Responsive Tracers

The development of pH-responsive tracers has recently gained notable interest. Such tracers are particularly useful for cancer diagnosis applications because of the well-known acidic extracellular pH of solid tumor microenvironment (6.8–7.2) compared with normal tissues (7.4). Moreover, lysosomal pH value can be as low as 4.5. pH-responsive polymer is a class of materials that undergo a change in solubility and hence conformation in response to pH. pH-responsive polymers can contain either acidic or basic residues, whose ionization depends on the pH of the surrounding medium. It is not surprising that basic pH-responsive polymers were the only pH-responsive ¹⁹F MRI tracers studied for cancer diagnostic applications, due to the acidic microenvironment of solid tumors, as explained earlier. For instance, Oishi et al. reported the synthesis of pH-responsive nanogel stabilized by poly­(ethylene glycol) (PEG) via emulsion copolymerization of 2-(N,N-diethylamino)­ethyl methacrylate (DEAMA) as pH-responsive monomer (pK _a ≈ 7.2–7.3), with TFEMA as fluorinated monomer at various molar ratios in the presence of divinyl cross-linker. The nanogel exhibited a remarkable OFF-ON switch of ¹⁹F MR signals in response to pH, due to the increase in the molecular motion of the fluorinated monomer through the deswelling-swelling (hydrophobic–hydrophilic) transition of the pH-responsive polyamine gel core in the pH range 7.3–6.8 (Figure a).

8.

(a) Schematic illustration of the OFF/ON ¹⁹MRI switch of PEGylated nanogel in response to pH-induced deswelling-swelling transition and its ¹⁹F MR signal at pH 6.5 and 7.4. Adapted with permission from ref . Copyright 2007, American Chemical Society (b) schematic illustration of OFF/ON ¹⁹F MRI switch of fluorinated micelles in response to pH-induced assembly disassembly transition, ¹⁹F MRI phantom images of poly­(ethylene oxide)-b-poly­[2-(diisopropylamino) ethyl methacrylate-r-trifluoroethyl methacrylate] (PEO-b-P­(DPA-r-TFE)) at pH 5.0 (inner tube) and 7.4 (outer tube), and SNR ratios of ¹H MRI and ¹⁹F MRI at pH 5.0 and 7.4. Adapted with permission from ref . Copyright 2013, John Wiley and Sons.

Wang et al. reported the synthesis of a series of star polymers with a branched core consisting of TFEA as fluorinated monomer and 2-(dimethylamino)­ethyl methacrylate (DMAEMA) as pH-responsive monomer (pK _a ≈ 7.4–7.8), and poly­(poly­(ethylene glycol) methyl ether methacrylate) (PPEGMA) arms, which form hydrophilic and biocompatible shells around the cores. A star polymer with a molar ratio of 1:7 [TFEA]/[DMAEMA] builds the basis of this study. ¹⁹F NMR signal intensity and T ₂ relaxation times were significantly dependent on the pH of the solution. T ₂ relaxation time significantly increased from T ₂ < 10 at pH 9 to T ₂ > 38 at pH 5, with almost constant T ₁ relaxation times of 450 at 11.75 T. A dramatic enhancement in ¹⁹F MRI signal intensity was only witnessed under acidic conditions (at pH below 6.5), as a result of improved mobility of fluorinated segments.

In the following year, the same group reported the synthesis of star polymers with a biodegradable cross-linked core consisting of bis­(2-methacryloyl)­oxyethyl disulfide (DSDMA) and arms consisting of DMAEMA and TFEMA. Substantial enhancement of ¹⁹F MRI T ₂ relaxation times and image intensity was witnessed upon a change in pH of the solution from 5 to 8, as a result of the deprotonation-protonation switch of DMAEMA units.

For the star polymer containing 2.3 wt % fluorine, the T ₂ relaxation time was 35 ms (11.7 T) at pH values below 6.5 but dropped sharply to less than 5 ms at pH 8. In contrast, the T ₁ relaxation time remained largely unaffected by changes in pH. In vitro ¹⁹F MRI suggested that these star polymers can be effectively imaged under acidic conditions; however, their imaging performance was limited at pH levels exceeding physiological conditions.

Huang et al. reported the synthesis of an elegant example of pH-responsive fluorinated diblock copolymer nanoparticles that undergo assembly disassembly transition in response to pH (Figure b). A series of diblock copolymers with a PEO hydrophilic block and a pH-responsive fluorinated block was synthesized using ATRP. The diblock copolymer self-assembled in water with fluorinated moieties confined within the poorly solvated pH-responsive block. At pH > pK _a, hydrophobic micelle assembly results in highly restricted chain motions, short T ₂ relaxation times, and attenuated ¹⁹F MRI signals (OFF signal). At pH < pK _a, protonation of tertiary amine groups caused micelle disassembly, conformational flexibility in the fluorinated polymer block, an enhancement in T ₂ relaxation time, and reappearance of the ¹⁹F MRI signal (ON signal). Similarly, Whittaker and co-workers reported the synthesis and evaluation of pH-responsive partly fluorinated statistical and block linear copolymers using TFEMA as a fluorinated monomer and DMAEMA as a pH-responsive monomer. Statistical copolymers were soluble in water, whereas block copolymers assembled into nanoparticles with PTFEMA cores and P­(TFEMA-co-DMAEMA) coronas. T ₂ relaxation times and ¹⁹F MRI performance of the nanoparticles were highly dependent on pH.

4.2. Redox-Responsive Tracers

Redox-responsive fluorinated polymers have recently emerged as a promising class of switchable tracers for ¹⁹F MRI, ,, taking advantage of the abnormal oxidative stress and elevated reductant levels in the tumor microenvironment. − Rather than generating constant ¹⁹F MRI signals, these systems are engineered to switch between “silent” and “active” ¹⁹F states in response to specific redox cues. So far, two main strategies have been investigated: (i) reactive oxygen species (ROS)-responsive polymers, and (ii) glutathione (GSH)-responsive polymers.

ROS-responsive systems often incorporate reductive-responsive moieties, such as thioethers, within fluorinated polymeric nanoparticles. These nanoparticles undergo oxidative transformation in the presence of elevated ROS (e.g., H₂O₂, ¹O₂), leading to nanoparticle dissociation into unimers and a substantial enhancement of the ¹⁹F signal. For example, Fu et al. reported the synthesis of fluorinated polymeric micelles that undergo assembly disassembly transition in response to ROS, and hence can be utilized as switchable ¹⁹F MRI tracers. The fluorinated polymers were synthesized via copolymerization of a thioether-containing monomer, namely 2-((2-((2-(ethylthio)­ethyl)­thio)­ethyl)­thio)­ethyl methacrylate (ETEMA), as ROS-monomer and TFEMA as fluorine-containing monomer using ATRP from a hydrophilic polyethylene glycol (PEG)-based initiator. Due to its amphiphilic nature, the fluorinated polymers self-assembled into polymeric micelles with poly­(2,2,2-trifluoroethyl methacrylate-co-2-((2-((2-(ethylthio)­ethyl)­thio)­ethyl)­thio)­ethyl methacrylate) (P­(TFEMA-co-ETEMA)) core. Upon exposure to H₂O₂, the hydrophobic thioether groups in the fluorinated polymer were oxidized to hydrophilic sulfoxide groups, leading to the disassembly of the micelles. The disassembly process enhanced the segmental motion of the fluorinated segments, thereby lengthening the ¹⁹F T ₂ relaxation times (T ₂ = 14–34 ms, 9.4T) and resulting in an intense ¹⁹F MRI signal.

Similarly, Chang et al. reported the synthesis of ROS-responsive polymeric fluorinated nanoparticles using a photopolymerization-induced self-assembly (photo-PISA) approach as illustrated in Figure . The PISA process involved the chain extension of a methoxy poly­(ethylene glycol) (mPEG)-based macro-CTA with ROS-responsive and fluorine-containing monomer, N-(2-((2,2,2-trifluoroethyl)­thio)­ethyl)­acrylamide (FTAM). The amphiphilic copolymer self-assembled to form spherical nanoparticles. In the nanoparticle form, the mobility of the fluorinated segment was significantly restricted, resulting in suppressed ¹⁹F MRI signals. Upon exposure to oxidants, the hydrophobic thioether groups in the PFTAM block were oxidized into hydrophilic sulfoxide groups. This oxidation triggers the disassembly of the nanoparticles, leading to a subsequent increase in the ¹⁹F MRI signal due to the enhanced mobility of the fluorinated segments.

9.

Schematic illustration of ¹⁹F MRI switchable (PEG-b-PFTAM) tracer with enhanced signal intensity in response to ROS. Reprinted with permission from ref . Copyright 2023, American Chemical Society.

More recently, Švec and colleagues reported an elegant example of redox-responsive fluorinated polymeric tracers that ¹⁹F MRI could visualize in both their reduced and oxidized states. In this system, a poly­(2-oxazoline)-based amphiphilic polymer was functionalized with fluorinated ferrocene moieties. In aqueous solution, the amphiphilic polymer self-assembled into micelles, with the ferrocene units located in the micellar core. In its reduced form, the fluorinated ferrocene (Fe²⁺) groups were diamagnetic (5 wt % fluorine, T ₁ = 620 ms and T ₂ = 8.2 ms). Upon exposure to ROS, the ferrocene groups were oxidized to positively charged paramagnetic ferrocenium (Fe³⁺), leading to disassembly of the micelles, accompanied by a substantial change in the chemical shift and relaxation times of the ¹⁹F nuclei (5 wt % fluorine, T ₁ = 280 ms, T ₂ = 20 ms). In vitro, the reduced and oxidized forms were visualized separately by ¹⁹F MRI.

In contrast, GSH-responsive polymers incorporate reductant-labile moieties such as disulfide or sulfone linkages. These linkages are cleaved in the reductive intracellular environment, producing lower-molecular-weight fragments or disassembled unimers with enhanced ¹⁹F signal intensity. For example, Huang et al. reported the development of fluorinated nanoparticles that were synthesized via RAFT polymerization of 2-((2,4-dinitro-N-(3,3,3-trifluoropropyl)­phenyl)­sulfonamido)-ethyl methacrylate (AMA-DNBS-F) monomer as a fluorine-containing and reduction-responsive monomer and mPEGMA as a hydrophilic monomer (Figure a). The statistical copolymers self-assembled to form nanoparticles with the fluorinated segments compactly packed into the hydrophobic core, resulting in a short T ₂ relaxation time and a poor ¹⁹F MRI signal “OFF”. Upon encountering thiols (e.g., cysteine, glutathione), the hydrophobic 2, 4-dinitrobenzenesulfonyl groups were excised, inducing significant disturbance of hydrophilic/hydrophobic balance, resulting in the disassembly of the nanoparticles with significant enhancement in T ₂ relaxation time of up to 296 ± 5.3 ms (9.4 T) and ¹⁹F MRI signals “ON”.

10.

(a) Schematic illustration of PPEGMA-b-P­(AMA-DNBS-F) as a ¹⁹F MRI reduction-responsive tracer and its in vivo ¹⁹F MR images. Reprinted with permission from ref . Copyright 2018, American Chemical Society. (b) Schematic illustration of (HFEA-co-GlcA-BAC) as hyper-branched reduction-responsive ¹⁹F MRI tracers and their ¹⁹F MRI performance. Adapted with permission from ref . Copyright 2019, American Chemical Society.

Tang et al. reported the synthesis of an amphiphilic polymer, consisting of PEG bearing a fluorinated end group via a disulfide linker, which self-assembled with NIR- absorbing indocyanine green (ICG) to form nanoparticles in aqueous solution. The nanoparticles underwent a stepwise redox-triggered and near-infrared (NIR) irradiation ON-OFF switch in ¹⁹F MRI signal intensity. Due to the molecular mobility restriction, the ¹⁹F NMR signal intensity of the self-assembled nanoparticles was negligible (OFF state). In the presence of GSH, the cleavage of disulfide linkers triggered morphology transition into ultrasmall nanoparticles, resulting in the first step activation of the ¹⁹F MRI signal (T ₂ = 136.4 ms). Absorption of NIR light by ICG molecules led to the complete disassociation of these ultrasmall nanoparticles into small hydrophilic molecules, resulting in a distinct second-step enhancement of the ¹⁹F NMR signal (T ₂ = 437.7 ms).

Fu et al. reported the synthesis of hyper-branched fluorinated glycosylated ¹⁹F MRI tracers that respond to a reductive environment, for cancer cells targeting (Figure b). The tracers were synthesized by RAFT polymerization of a fluorinated monomer, 2-((1,1,1,3,3,3-hexafluoropropan-2-yl)­oxy)­ethyl acrylate (HFEA), and a d-glucose glycomonomer (GlcA) in the presence of a disulfide-containing cross-linking monomer N,N′-bis­(acryloyl)­cystamine (BAC). The presence of the glucose moiety facilitated receptor-mediated cellular uptake by cancer cells due to its interactions with the overexpressed sugar transporters on the cell surface.

Furthermore, the tracers demonstrated an enhanced ¹⁹F MRI signal in response to a reducing microenvironment, as a result of an architectural transformation from a branched structure (T ₂ = 26 −15 ms, 9.4 T) to low molecular weight linear polymer chains. This structural transition led to a significant enhancement in ¹⁹F MRI signal intensity (T ₂ = 46–21 ms).

4.3. Thermoresponsive Tracers

The design of thermoresponsive polymeric tracers has received significant interest as ¹⁹F MRI tracers. Thermoresponsive polymers are a class of polymers that exhibit pronounced, reversible changes in their solution behavior in response to temperature. Thermal transitions of polymer solutions can generally be categorized into two main classes based on their phase transition behavior: lower critical solution temperature (LCST) type and upper critical solution temperature (UCST) type. LCST-type polymers undergo reversible phase separation from homogeneous solution upon heating above the LCST. , In contrast, UCST-type polymers exhibit reversible phase separation of the polymer upon cooling below a critical temperature. , Only partially fluorinated polymers with LCST-type transition have been designed and examined as ¹⁹F MRI tracers. ,,,, Poly­[N-(2,2-difluoroethyl)­acrylamide] (PDFEA), with two chemically equivalent fluorine atoms, is perhaps the most reported LCST-type thermoresponsive polymer for ¹⁹F MRI applications.

PDFEA was first synthesized by Bak and co-workers in 2012, who reported an LCST of around 26 °C in pure water. However, the LCST of PDFEA in physiologically relevant solutions (e.g., PBS) has been reported to be much lower. Furthermore, the LCST of PDFEA can be influenced by several structural factors, including molecular weight, end-group functionality, and copolymerization with either hydrophobic or hydrophilic comonomers. ,,,

Above its LCST, PDFEA forms a homogeneous solution due to extensive hydrogen bonding between the polymer and surrounding water molecules, resulting in an enthalpic contribution that dominates and causes the dissolution of polymer chains. Above its LCST, the hydrogen bonds with water molecules weaken, while intra- and intermolecular hydrogen bonding within the polymer chain dominates, thereby increasing the entropic contribution and causing phase separation.

The main advantage of using amphiphilic copolymers with a PDFEA thermoresponsive block in drug delivery and theranostic applications is their ability to be injected into the human body at room temperature in an aqueous solution, while forming nanoparticles with a PDFEA block core upon heating to body temperature. This approach avoids the use of water-miscible biocompatible organic solvents (e.g., dimethyl sulfoxide) for the injection of an amphiphilic copolymer that would self-assemble within the body due to solvent shift. For example, Kolouchova et al. reported the synthesis of a library of thermoresponsive polymeric nanoparticles comprising a hydrophilic poly­[N-(2-hydroxypropyl)­methacrylamide] (PHPMA) or poly­(2-methyl-2-oxazoline) (PMeOx) block, and a thermoresponsive PDFEA block. The thermoresponsive properties of the PDFEA block allow the self-assembly of nanoparticles upon heating in an aqueous solution. A high concentration of magnetically equivalent fluorine atoms (18.7 wt %) resulted in a sharp ¹⁹F NMR signal with good ¹⁹F MRI performance, despite their location within the core of the nanoparticles. While increasing temperature can significantly shorten T ₂ relaxation times and hence reduce ¹⁹F MRI signal intensity due to the change in fluorine atoms’ mobility within the polymer chain, the ¹⁹F MRI signal is still detectable with good sensitivity because of sufficient solvation of fluorine atoms.

In the following few years, the same group reported the synthesis of a series of BAB triblock copolymers, where B corresponds to thermoresponsive PDFEA blocks and A is a hydrophilic poly­(ethylene glycol) block. These BAB triblock copolymers self-assembled into either flower-like nanoparticles or cross-linked hydrogel in dilute aqueous solutions with increasing temperature. The hydrogel demonstrated decent ¹⁹F MRI performance.

Nevertheless, these LCST-type thermoresponsive ¹⁹F MRI tracers usually do not enhance the disassembly of the nanoparticles for switchable ¹⁹F MRI properties or potential drug release. Therefore, additional stimuli-responsive moieties can be introduced to trigger the disassembly of these nanoparticles within the tumor microenvironment. Kolouchova et al. reported the synthesis of thermo- and ROS-responsive diblock copolymer with PHPMA water-soluble block and poly­(N-(2,2-difluoroethyl)­acrylamide-co-(ferrocenylcarboxamido)­ethyl acrylamide) P­(DFEA-co-FcCFA) as dual responsive hydrophobic block. The diblock copolymer formed nanoparticles when heated in an aqueous solution above 33 °C, but disassembles when exposed to ROS conditions due to a switch from a hydrophobic (Fe­(II), ferrocene) reduced state to a hydrophilic (Fe­(III), ferrocenium cation) oxidized state. T ₁ and T ₂ relaxation times decreased with the increase in ferrocene content; therefore, only the diblock copolymer system with a low concentration of ferrocene was further investigated. The diblock copolymer was utilized to load hydrophobic drugs (e.g., doxorubicin (DOX)) in its reduced state and release them in its oxidized state, while maintaining appropriate ¹⁹F MRI properties. Moreover, the oxidation of the diamagnetic ferrocene to paramagnetic ferrocenium did not affect ⁹F MRI performance.

Sedllacek and co-workers reported the synthesis of a dual pH- and thermoresponsive statistical copolymer by RAFT copolymerization of DFEAM with N-(3-imidazol-1-ylpropyl)­acrylamide (ImPAM). ,, This dual-responsive copolymer was injected into the body as a slightly acidic aqueous solution. Once injected into the body, deprotonation of the imidazole group occurred, leading to phase separation triggered by the LCST effect (Figure ). The study revealed a strong dependence of the ¹⁹F MRI performance on increasing temperature. Low ¹⁹F MRI signal intensity and broad peak line width were observed with increasing temperature, presumably due to the change in fluorine atoms’ mobility above their cloud temperature. Nevertheless, the MRI intensity remained high enough and was further investigated for in vivo ¹⁹F MRI measurements.

11.

Schematic illustration of the dual pH-/thermos-responsive injectable implant formation. Reproduced with permission from ref . Copyright 2018, American Chemical Society.

Despite several successful examples of LCST-type fluorinated polymers reported earlier in this review, these systems primarily phase-separate upon heating, and hence do not provide an actual switch in ¹⁹F MRI signal intensity. There is a growing need for the design of UCST-type thermoresponsive fluorinated polymers for switchable ¹⁹F MRI tracers. Unlike LCST-type systems, UCST-type amphiphilic copolymer solutions self-assemble into micelles below a critical temperature and therefore produce no detectable (OFF) ¹⁹F MRI signal. When the temperature exceeds the UCST, these micelles dissociate into unimer, leading to signal activation (ON). This signal switch is particularly advantageous for cancer diagnosis, as tumor tissues often reveal slightly elevated local temperatures due to increased metabolic activity and inflammation. Therefore, UCST-type amphiphilic copolymers allow highly selective, site-specific ¹⁹F MRI signal activation in tumor regions, while minimizing background signals in surrounding healthy tissues.

4.4. Enzyme-Responsive Tracers

Cancerous tissues exhibit a unique enzymatic profile compared to normal cells. Certain enzymes (e.g., matrix metalloproteinases, cathepsins) are often overexpressed within tumors. To date, only a single example of enzyme-responsive polymers for ¹⁹F MRI applications has been reported. The reported example relies on the attachment of fluorinated moieties into polymer chains via an enzyme-cleavable linkage. In this work, Buzhor et al. designed an amphiphilic hybrid ¹⁹F MRI tracer based on a hydrophilic PEG block and a hydrophobic enzyme-responsive dendron that self-assembled into smart micelles. Two types of molecular architectures were investigated: one with cleavable fluorinated moieties and another with noncleavable fluorinated labels but with cleavable hydrophobic end groups. In a system with cleavable fluorinated end groups, small fluorinated molecules were released in the presence of porcine liver esterase, resulting in a remarkable enhancement in T ₂ relaxation times and an intense ¹⁹F MRI signal. In a system with noncleavable fluorinated labels, ¹⁹F NRI signal activation was obtained via micelle disassembly upon cleavage of the hydrophobic end groups.

5. Fluorinated Polymers for ¹⁹F MRI Theranostic Applications

¹⁹F MRI theranostics, which combine diagnostic and therapeutic capabilities, have recently garnered significant interest due to their potential for personalized medicine and targeted cancer therapies. An example of a fluorinated chemotherapeutic drug conjugated into a polymer backbone via an enzyme-cleavable linker for ¹⁹F MRI theranostic applications was reported by Alhaidari and Spain. In this study, 5-Fluorouracil (a model fluorinated drug) was conjugated into hydrophilic hyper-branched poly­(N,N-dimethylacrylamide) (PDMA) via enzyme-cleavable peptide linkers. The 5-FU polymer conjugate exhibited a broad ¹⁹F NMR signal and a short T ₂ relaxation time (T ₂ = 38 ms, 9.4 T). Incubation with S9 fractions induced the release of 5-FU, accompanied by an extension of T ₂ relaxation times (T ₂ = 148 ms) and a sharp ¹⁹F NMR signal. Nevertheless, due to the low 5-FU release of 9%, further evaluation of 5-FU release using ¹⁹F MRI phantom imaging was not possible.

Conjugating hydrophobic drugs to a partially fluorinated polymer backbone increased the overall hydrophobicity of the polymer conjugates. Meanwhile, the release of these hydrophobic drugs significantly enhanced the hydrophilicity of the polymer, resulting in improved ¹⁹F MRI performance. For example, Fuchs et al. reported the synthesis of a switchable hyperbranched polymeric ¹⁹F MRI tracer with pH and redox-cleavable linkage that is capable of quantifying drug release (Figure a). The hyperbranched polymer consisted of poly­(ethylene glycol) monomethyl ether methacrylate (PEGMA), TFEA as a fluorinated monomer, and an appropriate monomer for postconjugation of different hydrophobic drugs. The hydrophobic drugs, including DOX, docetaxel (DTX), and camptothecin (CPT), were conjugated to the hyperbranched polymers via an acid-cleavable hydrazone linkage or a redox-cleavable disulfide linkage. The study concluded that the incorporation of the hydrophobic drug resulted in restricted motion of the fluorinated moieties, leading to a decrease in T ₂ relaxation times (T ₂ = 9.1–10.9 ms, 9.4T) and a reduction in ¹⁹F MRI image intensity. However, drug release resulted in an increase in T ₂ relaxation times (T ₂ = 13.8–14.6 ms) and ¹⁹F MRI image intensity due to the enhanced mobility of the fluorinated moieties within the hyperbranched polymer.

12.

(a) Schematic illustration of ¹⁹F MRI signal intensity switch induced by release of hydrophobic drug upon cleavage of pH and ROS linkages. Adapted with permission from ref . Copyright 2017, Royal Society of Chemistry. (b) Release of the hydrophobic drug increased the overall LCST of the thermoresponsive fluorinated polymer, enhancing the ¹⁹F MRI signal intensity. Adapted with permission from ref . Copyright 2021, Royal Society of Chemistry.

Usman et al. reported the synthesis and evaluation of a series of statistical terpolymers consisting of styrene as hydrophobic monomer, oligoethylene glycol methyl ether methacrylate (OEGMA) as LCST-type thermoresponsive based polymer, and TFEA as fluorinated monomer (Figure b). Tuning styrene content resulted in an LCST close to physiological temperature. As expected, above the LCST, the ¹⁹F MR imaging intensity dropped as a result of enhanced dipolar interactions with other ¹⁹F nuclei. Moreover, the authors further investigated this thermoresponsive system for switchable ¹⁹F MRI theranostic applications by incorporating a hydrophobic drug through an acid-cleavable hydrazone linkage. It was verified that with the release of the hydrophobic drug, the LCST of the polymer was raised due to decreasing overall hydrophobicity, enhancing the ¹⁹F MRI signal intensity.

6. Conclusion

This review summarizes the current state of partially fluorinated polymers as a next-generation platform for ¹⁹F MRI tracers. Partially fluorinated polymers have emerged as a versatile and promising class of tracers for ¹⁹F MRI, offering unique advantages such as tunable signal intensity, improved biocompatibility, and enhanced formulation stability compared to conventional perfluorocarbon emulsions. Their macromolecular design allows for precise control over fluorine content, polymer architecture, and responsiveness to physiological stimuli, enabling switchable and highly sensitive ¹⁹F MRI signals. Recent advances, particularly in stimuli-responsive systems (e.g., pH, ROS- or redox-activated polymers), highlight their potential for real-time, disease-specific diagnostics and therapy monitoring. Continued development in the design of partially fluorinated polymers will further expand their clinical translation and impact in precision diagnostics and personalized medicine.

The author declares no competing financial interest.