19F Magnetic Resonance Research Articles

Superhydrophilic Fluorinated Polymer Probe for Zero-Background 19F MRI with Adaptable Targeting Ability.

19F magnetic resonance imaging (19F MRI), with zero background, high tissue penetration depth, excellent spatial resolution, and nonradioactive features, has attracted considerable attention but faces tough challenges due to the shortage of sensitive and selective targetable probes. Herein, we report a biocompatible and highly sensitive 19F MRI probe with an adaptable tumor-targeting ability. The fluorine-grafted polymer (PIBMA-FSON) probes were rich with sulfoxide and carboxy groups, containing a high fluorine content (∼17 wt %). The probes exhibit superhydrophilicity, strong 19F MRI signals (enhancement of ∼95-fold), long transverse relaxation time (T2, 422 ms), and excellent 19F MRI capability. Conjugation using a targeting peptide (Arg-Gly-Asp, RGD) afforded ultrasmall soft polymer probes (PIBMA-FSON-RGD) with superhydrophilicity and tumor-targeting ability suitable for the 19F MRI of orthotopic bladder cancer. Amidification of 5% of the carboxylate units with oleylamine resulted in PIBMAOAm-FSON nanoprobes (NPs) via self-assembly, displaying different targeting toward subcutaneous tumors. Further grafting with near-infrared (NIR) dyes renders the probe suitable for NIR-fluorescence and 19F MRI dual-modality imaging. This study provides a suitable approach for designing highly sensitive and zero-background 19F MRI probes with a tunable tumor-targeting ability.

Fine-Tuned "Click" Functionalization of PAMAM Dendrimers with a Linear Fluorinated Guanidino Linker: Synthesis, Characterization, and Applications.

This study presents the synthesis, characterization, and application of multifunctional PAMAM G2 and G4 dendrimers decorated with a linear fluorinated guanidino linker designed to improve gene delivery efficiency while minimizing cytotoxicity. For the first time, we were able to fine-tune the degree of grafting (DG) during the functionalization process through efficient "click" Michael addition, achieving the synthesis of a collection of six PAMAM conjugates that showed a significant enhancement in transfection efficiency (TE), surpassing the performance of traditional nonviral vectors. The incorporation of fluorinated moieties not only facilitated better deoxyribonucleic acid (DNA) condensation and TE but also introduced potential applications in 19F magnetic resonance imaging thanks to the sharp and intense fluorine nuclear magnetic resonance signals and favorable relaxation parameters. The new dendrimer conjugates demonstrated a promising balance between low cytotoxicity and high TE, with the low-generation PAMAM G2 with lower DG being the best-performing conjugate, making them strong candidates for further development in gene therapy. These findings highlight the potential of these multifunctional PAMAM dendrimers as efficient, nontoxic, and trackable gene delivery vectors.

Stimuli-Responsive Polymers for Advanced 19F Magnetic Resonance Imaging: From Chemical Design to Biomedical Applications.

Fluorine magnetic resonance imaging (19F MRI) is a rapidly evolving research area with a high potential to advance the field of clinical diagnostics. In this review, we provide an overview of the recent progress in the field of fluorinated stimuli-responsive polymers applied as 19F MRI tracers. These polymers respond to internal or external stimuli (e.g., temperature, pH, oxidative stress, and specific molecules) by altering their physicochemical properties, such as self-assembly, drug release, and polymer degradation. Incorporating noninvasive 19F labels enables us to track the biodistribution of such polymers. Furthermore, by triggering polymer transformation, we can induce changes in 19F MRI signals, including attenuation, amplification, and chemical shift changes, to monitor alterations in the environment of the tracer. Ultimately, this review highlights the emerging potential of stimuli-responsive fluoropolymer 19F MRI tracers in the current context of polymer diagnostics research.

Hyperbranched Polymeric 19F MRI Contrast Agents with Long T2 Relaxation Time Based on β-Cyclodextrin and Phosphorycholine.

19F magnetic resonance imaging (19F MRI) is gaining attention as an emerging diagnostic technology. Effective 19F MRI contrast agents (CAs) for in vivo applications require a long transverse (or spin-spin) relaxation time (T2), short longitudinal (or spin-lattice) relaxation time (T1), high fluorine content, and excellent biocompatibility. Here, we present a novel hyperbranched polymeric 19F MRI CA based on β-cyclodextrin and phosphorylcholine. The influence of the branching degree and fluorine content on T2 was thoroughly investigated. Results demonstrated a maximum fluorine content of 11.85% and a T2 of 612 ms. This hyperbranched polymeric 19F MRI CA exhibited both great biocompatibility against cells and organs of mice and high-performance imaging capabilities both in vitro and in vivo. The research provides positive insights into the synthesis strategies, topological design, and selection of fluorine tags for 19F MRI CAs.

Fluorinated PAMAM-Arginine Carrier Prodrugs for pH-Sensitive Sustained Ibuprofen Delivery

ObjectiveThe development of an efficient, multifunctional drug delivery system overcoming different obstacles generally associated with drug formulations, including the poor accumulation of the active principle in the target site and its sustained release for prolonged time.MethodsOur study proposes the development of a fluorinated poly(amidoamine) (PAMAM) carrier prodrug combining drug release boosted in alkaline environments with a possible implementation in 19F MRI applications. In particular, we functionalized the terminal primary amines of PAMAM G2 and G4 through an ad hoc designed fluorinated ibuprofen-arginine Michael acceptor to obtain multifunctional ibuprofen-PAMAM-Arg conjugates.ResultsThese carriers demonstrated pH-dependent and sustained ibuprofen release for more than 5 days. This advantage was observed in both weak alkaline and physiological buffer solutions, allowing to overcome the limits associated to the burst release from similar fluorinated Arg-PAMAM dendrimers with ibuprofen physically encapsulated.ConclusionThese findings, coupled to the high biocompatibility of the system, suggest a potential synergistic biomedical application of our conjugates, serving as vehicles for drug delivery and as 19F magnetic resonance imaging contrast agents.

Fluorinated 1,7-DO2A-Based Iron(II) Complexes as Sensitive 19F MRI Molecular Probes for Visualizing Renal Dysfunction in Living Mice.

Kidney diseases have become an important global health concern due to their high incidence, inefficient diagnosis, and poor prognosis. Devising direct methods, especially imaging means, to assess renal function is the key for better understanding the mechanisms of various kidney diseases and subsequent development of effective treatment. Herein, we developed a fluorinated ferrous chelate-based sensitive probe, 1,7-DO2A-Fe(II)-F18 (Probe 1), for 19F magnetic resonance imaging (MRI). This highly fluorinated probe (containing 18 chemically equivalent 19F atoms with a fluorine content at 35 wt %) achieves a 15-time enhancement in signal intensity compared with the fluorine-containing ligand alone due to the appropriately regulated 19F relaxation times by the ferrous ion, which significantly increases imaging sensitivity and reduces acquisition time. Owing to its high aqueous solubility, biostability, and biocompatibility, this probe could be rapidly cleared by kidneys, which provides a means for monitoring renal dysfunction via 19F MRI. With this probe, we accomplish in vivo imaging of the impaired renal dysfunction caused by various kidney diseases including acute kidney injury, unilateral ureteral obstruction, and renal fibrosis at different stages. Our study illustrates the promising potential of Probe 1 for in vivo real-time visualization of kidney dysfunction, which is beneficial for the study, diagnosis, and even stratification of different kidney diseases. Furthermore, the design strategy of our probe is inspiring for the development of more high-performance 19F MRI probes for monitoring various biological processes.

A pH-responsive nanoplatform with dual-modality imaging for enhanced cancer phototherapy and diagnosis of lung metastasis.

To address the limitations of traditional photothermal therapy (PTT)/ photodynamic therapy (PDT) and real-time cancer metastasis detection, a pH-responsive nanoplatform (NP) with dual-modality imaging capability was rationally designed. Herein, 1H,1H-undecafluorohexylamine (PFC), served as both an oxygen carrier and a 19F magnetic resonance imaging (MRI) probe, and photosensitizer indocyanine green (ICG) were grafted onto the pH-responsive peptide hexahistidine (H6) to form H6-PFC-ICG (HPI). Subsequently, the heat shock protein 90 inhibitor, gambogic acid (GA), was incorporated into hyaluronic acid (HA) modified HPI (HHPI), yielding the ultimate HHPI@GA NPs. Upon self-assembly, HHPI@GA NPs passively accumulated in tumor tissues, facilitating oxygen release and HA-mediated cell uptake. Once phagocytosed by lysosomes, protonation of H6 was triggered due to the low pH, resulting in the release of GA. With near-infrared laser irradiation, GA-mediated decreased HSP90 expression and PFC-mediated increased ROS generation amplified the PTT/PDT effect of HHPI@GA, leading to excellent in vitro and in vivo anticancer efficacies. Additionally, the fluorescence and 19F MRI dual-imaging capabilities of HHPI@GA NPs enabled effective real-time primary cancer and lung metastasis monitoring. This work offers a novel approach for enhanced cancer phototherapy, as well as precise cancer diagnosis.

Small molecule probes for the specific imaging of monoamine oxidase A and monoamine oxidase B

AbstractMonoamine oxidases (MAOs) are a class of flavin enzymes that are mainly present in the outer membrane of mitochondria and play a crucial role in maintaining the homeostasis of monoamine neurotransmitters in the central nervous system. Furthermore, expression of MAOs is associated with the functions of peripheral organs. Dysfunction of MAOs is relevant in a variety of diseases such as neurodegenerative diseases, heart failure, metabolic disorders, and cancers. Monoamine oxidases have two isoenzymes, namely, monoamine oxidase A (MAO‐A) and monoamine oxidase B (MAO‐B). Therefore, the development of reliable and specific methods to detect these two isoenzymes is of great significance for the in‐depth understanding of their functions in biological systems, and for further promoting the clinical diagnosis and treatment of MAO‐related diseases. This review mainly focuses on the advances in small molecular probes for the specific imaging of MAO‐A and MAO‐B, including radiolabeled probes, fluorescent probes, and a 19F magnetic resonance imaging probe. In addition, applications of these probes for detecting MAO expression levels in cells, tissues, animal models, and patients are described. Finally, the challenges and perspectives of developing novel MAO imaging probes are also highlighted.

Visualization and Quantification of Drug Release by GSH-Responsive Multimodal Integrated Micelles.

Using molecular imaging techniques to monitor biomarkers and drug release profiles simultaneously is highly advantageous for cancer diagnosis and treatment. However, achieving the accurate quantification of both biomarkers and drug release with a single imaging modality is challenging. This study presents the development of a glutathione (GSH)-responsive polymer-based micelle, PEG-SS-FCy7/PEG-SS-GEM (PSFG), which can precisely localize the tumor using bimodal imaging and prevent drug leakage. These PSFG micelles exhibit a small particle size of 106.3 ± 12.7 nm with a uniform size distribution, and the drug loading efficiency can also be easily controlled by changing the PEG-SS-FCy7 (PSF) and PEG-SS-GEM (PSG) feeding ratio. The PSFG micelles display weak fluorescence emission and minimal drug release under physiological conditions but collapse in the presence of GSH to trigger near-infrared fluorescence and the 19F magnetic resonance imaging signal, allowing for real-time monitoring of intracellular GSH levels and drug release. GSH could synergistically promote the disassembly of the micellar structure, resulting in accelerated probe and drug release of up to about 93.1% after 24 h. These prodrug micelles exhibit high in vitro and in vivo antitumor abilities with minimal side effects. The GSH-responsive drug delivery system with dual-modal imaging capability provides a promising imaging-guided chemotherapeutic platform to probe the tumor microenvironment and quantify real-time drug release profiles with minimal side effects.

Superfluorinated, Highly Water-Soluble Polyphosphazenes as Potential 19F Magnetic Resonance Imaging (MRI) Contrast Agents.

"Hot spot" 19F magnetic resonance imaging (MRI) has garnered significant attention recently for its ability to image various disease markers quantitatively. Unlike conventional gadolinium-based MRI contrast agents, which rely on proton signal modulation, 19F-MRI's direct detection has a unique advantage in vivo, as the human body exhibits a negligible background 19F-signal. However, existing perfluorocarbon (PFC) or PFC-based contrast materials suffer from several limitations, including low longitudinal relaxation rates and relatively low imaging efficiency. Hence, we designed a macromolecular contrast agent featuring a high number of magnetically equivalent 19F-nuclei in a single macromolecule, adequate fluorine nucleus mobility, and excellent water solubility. This design utilizes superfluorinated polyphosphazene (PPz) polymers as the 19F-source; these are modified with sodium mercaptoethanesulfonate (MESNa) to achieve water solubility exceeding 360 mg/mL, which is a similar solubility to that of sodium chloride. We observed substantial signal enhancement in MRI with these novel macromolecular carriers compared to non-enhanced surroundings and aqueous trifluoroacetic acid (TFA) used as a positive control. In conclusion, these novel water-soluble macromolecular carriers represent a promising platform for future MRI contrast agents.

Multivalent Fluorinated Nanorings for On-Cell 19F NMR.

The design of imaging agents with a high fluorine content is necessary for overcoming the challenges of low sensitivity in 19F magnetic resonance imaging (MRI)-based molecular imaging. Chemically self-assembled nanorings (CSANs) provide a strategy to increase the fluorine content through multivalent display. We previously reported an 19F NMR-based imaging tracer, in which case a CSAN-compatible epidermal growth factor receptor (EGFR)-targeting protein E1-dimeric dihydrofolate (E1-DD) was bioconjugated to a highly fluorinated peptide. Despite good 19F NMR performance in aqueous solutions, a limited signal was observed in cell-based 19F NMR using this monomeric construct, motivating further design. Here, we design several new E1-DD proteins bioconjugated to peptides of different fluorine contents. Flow cytometry analysis was used to assess the effect of variable fluorinated peptide sequences on the cellular binding characteristics. Structure-optimized protein, RTC-3, displayed an optimal spectral performance with high affinity and specificity for EGFR-overexpressing cells. To further improve the fluorine content, we next engineered monomeric RTC-3 into CSAN, η-RTC-3. With an approximate eightfold increase in the fluorine content, multivalent η-RTC-3 maintained high cellular specificity and optimal 19F NMR spectral behavior. Importantly, the first cell-based 19F NMR spectra of η-RTC-3 were obtained bound to EGFR-expressing A431 cells, showing a significant amplification in the signal. This new design illustrated the potential of multivalent fluorinated CSANs for future 19F MRI molecular imaging applications.

Detection of sub-nmol amounts of the antiviral drug favipiravir in 19F MRI using photo-chemically induced dynamic nuclear polarization

In biological tissues, 19F magnetic resonance (MR) enables the non-invasive, background-free detection of 19F-containing biomarkers. However, the signal-to-noise ratio (SNR) is usually low because biomarkers are typically present at low concentrations. Measurements at low magnetic fields further reduce the SNR. In a proof-of-principal study we applied LED-based photo-chemically induced dynamic nuclear polarization (photo-CIDNP) to amplify the 19F signal at 0.6 T. For the first time, 19F MR imaging (MRI) and spectroscopy (MRS) of a fully biocompatible model system containing the antiviral drug favipiravir has been successfully performed. This fluorinated drug has been used to treat Ebola and COVID-19. Since the partially cyclic reaction scheme for photo-CIDNP allows for multiple data acquisitions, averaging further improved the SNR. The mean signal gain factor for 19F has been estimated to be in the order of 103. An in-plane resolution of 0.39 × 0.39 mm2 enabled the analysis of spatially varying degrees of hyperpolarization. The minimal detectable amount of favipiravir per voxel was estimated to about 500 pmol. The results show that 19F photo-CIDNP is a promising method for the non-invasive detection of suitable 19F-containing drugs and other compounds with very low levels of the substance.

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

19F magnetic resonance (19F MR) tracers stand out for their wide range of applications in experimental and clinical medicine, as they can be precisely located in living tissues with negligible fluorine background. This contribution demonstrates the long-term dissolution of multiresponsive fluorinated implants designed for prolonged release. Implants were detected for 14 (intramuscular injection) and 20 (subcutaneous injection) months by 19F MR at 4.7 T, showing favorable MR relaxation times, biochemical stability, biological compatibility and slow, long-term dissolution. Thus, polymeric implants may become a platform for long-term local theranostics.

Vanadium(V) complexes derived from triphenylphosphonium and hydrazides: cytotoxicity evaluation and interaction with biomolecules.

The development of coordination compounds with antineoplastic therapeutic properties is currently focused on non-covalent interactions with deoxyribonucleic acid (DNA). Additionally, the interaction profiles of these compounds with globular plasma proteins, particularly serum albumin, warrant thorough evaluation. In this study, we report on the interactions between biomolecules and complexes featuring hydrazone-type imine ligands coordinated with vanadium. The potential to enhance the therapeutic efficiency of these compounds through mitochondrial targeting is explored. This targeting is facilitated by the derivatization of ligands with triphenylphosphonium groups. Thus, this work presents the synthesis, characterization, interactions, and cytotoxicity of dioxidovanadium(V) complexes (C1-C5) with a triphenylphosphonium moiety. These VV-species are coordinated to hydrazone-type iminic ligands derived from (3-formyl-4-hydroxybenzyl)triphenylphosphonium chloride ([AH]Cl) and aromatic hydrazides ([H2L1]Cl-[H2L5]Cl). The structures of the five complexes were elucidated through single-crystal X-ray diffraction and vibrational spectroscopies, confirming the presence of dioxidovanadium(V) species in various geometries with degrees of distortion (τ = 0.03-0.50) and highlighting their zwitterionic characteristics. The molecular structural stability of C1-C5 in solution was ascertained using 1H, 19F, 31P, and 51V-nuclear magnetic resonance. Moreover, their interactions with biomolecules were evaluated using diverse spectroscopic methodologies and molecular docking, indicating moderate interactions (Kb ≈ 104 M-1) with calf thymus DNA in the minor groove and with human serum albumin, predominantly in the superficial IB subdomain. Lastly, the cytotoxic potentials of these complexes were assessed in keratinocytes of the HaCaT lineage, revealing that C1-C5 induce a reduction in metabolic activity and cell viability through apoptotic pathways.

Visualization of drug release in a chemo-immunotherapy nanoplatform via ratiometric 19F magnetic resonance imaging.

Visualization of drug release in vivo is crucial for improving therapeutic efficacy and preventing inappropriate medication dosing, yet, challenging. Herein, we report a pH-activated chemo-immunotherapy nanoplatform with visualization of drug release in vivo by ratiometric 19F magnetic resonance imaging (19F MRI). This nanoplatform consists of ultra-small histamine-modified perfluoro-15-crown-5-ether (PFCE) nanodroplets loaded with doxorubicin (Dox), which are packaged in trifluoromethyl-containing metal-organic assemblies via coordination-driven self-assembly. The chemical shifts of two types of 19F atoms in the nanoplatform are significantly different in 19F nuclear magnetic resonance (NMR) spectra, which facilitates the implementation of ratiometric 19F MRI without any signal crosstalk. In an acidic tumor microenvironment, this nanoplatform gradually degrades, which results in a sustained drug release with a real-time change in the ratiometric 19F MRI signal. Therefore, a linear correlation between the Dox release profile and ratiometric 19F MRI signal is established to visualize Dox release. Moreover, the pH-triggered disassembly of the nanoplatform leads to cell pyroptosis, which evokes immunogenic cell death (ICD), resulting in the regression of the primary tumor and inhibition of distal tumor growth. This study provides the proof-of-concept application of ratiometric 19F MRI to visualize drug release in vivo.

Transition metal complexes of the (2,2,2-trifluoroethyl)phosphinate NOTA analogue as potential contrast agents for 19F magnetic resonance imaging.

A new hexadentate 1,4,7-triazacyclononane-based ligand bearing three coordinating methylene-(2,2,2-trifluoroethyl)phosphinate pendant arms was synthesized and its coordination behaviour towards selected divalent (Mg2+, Ca2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+) and trivalent (Cr3+, Fe3+, Co3+) transition metal ions was studied. The ligand forms stable complexes with late divalent transition metal ions (from Co2+ to Zn2+) and the complexes of these metal ions are formed above pH ∼3. A number of complexes with divalent metal ions were structurally characterized by means of single-crystal X-ray diffraction. The complex of the larger Mn2+ ion adopts a twisted trigonally antiprismatic geometry with a larger coordination cavity and smaller torsion of the pendant arms, whereas the smaller ions Ni2+, Cu2+ and Zn2+ form octahedral species with a smaller cavity and larger pendant arm torsion. In the case of the Co2+ complexes, both coordination arrangements were observed. The complexes with paramagnetic metal ions were studied from the point of view of potential utilization in 19F magnetic resonance imaging. A significant shortening of the 19F NMR longitudinal relaxation times was observed: a sub-millisecond range for complexes of Cr3+, Mn2+ and Fe3+ with symmetric electronic states (t2g3 and HS-d5), the millisecond range for the Ni2+ and Cu2+ complexes and tens of milliseconds for the Co2+ complex. Such short relaxation times are consistent with a short distance between the paramagnetic metal ion and the fluorine atoms (∼5.5-6.5 Å). Among the redox-active complexes (Mn3+/Mn2+, Fe3+/Fe2+, Co3+/Co2+, Cu2+/Cu+), the cobalt complexes show sufficient stability and a paramagnetic-diamagnetic changeover with the redox potential lying in a physiologically relevant range. Thus, the Co3+/Co2+ complex pair can be potentially used as a smart redox-responsive contrast agent for 19F MRI.

Synthesis of fluorinated curcumin derivatives for detecting amyloid plaques by 19F-MRI.

The most prominent pathophysiological hallmark of Alzheimer's disease is the aggregation of amyloid-β (Aβ) peptides into senile plaques. Curcumin and its derivatives exhibit a high affinity for binding to Aβ fibrils, effectively inhibiting their growth. This property holds promise for both therapeutic applications and diagnostic molecular imaging. In this study, curcumin was functionalized with perfluoro-tert-butyl groups to create candidate molecular probes specifically targeted to Aβ fibrils for use in 19F-magnetic resonance imaging. Two types of fluorinated derivatives were considered: mono-substituted (containing nine fluorine atoms per molecule) and disubstituted (containing eighteen fluorine atoms). The linker connecting the perfluoro moiety with the curcumin scaffold was evaluated for its impact on binding affinity and water solubility. All mono-substituted compounds and one disubstituted compound exhibited a binding affinity toward Aβ fibrils on the same order of magnitude as reference curcumin. The insertion of a charged carboxylate group into the linker enhanced the water solubility of the probes. Compound Curc-Glu-F9 (with one L-glutamyl moiety and a perfluoro-tert-butyl group), showed the best properties in terms of binding affinity towards Aβ fibrils, water solubility, and intensity of the 19F-NMR signal in the Aβ oligomer bound form.

A versatile nano-transformer for efficient localization-specific imaging and synergistic therapy of bladder cancer

A stepwise morphologic transformation is highly desirable but rarely reported for promoting drug penetration at tumor sites via reducing transport barriers. Herein, an adhesive multifunctional nano-transformer (CTMF NPs) with cascading structural transformation was constructed, which afforded tumor microenvironment (TME)-activatable zero-background 19F-magnetic resonance imaging and ratiometric photoacoustic imaging-guided synergistic tumor therapy. CTMF NPs were synthesized via a one-pot encapsulation and dynamic coordination strategy, where copper sulfide nanoparticles (CuS NPs, photothermal agent) were co-encapsulated with perfluoro-15-crown-5-ether (PFCE, 19F MRI agent) by the dopamine grafted amphiphilic polymer, followed by coating with metal (Mn2+)-polyphenol shell (19F signal quencher and therapeutic agent). Benefiting from polyphenol enhanced cell adherence as well as in situ generated reactive quinone, the CTMF NPs attached to tumor sites and exhibited efficient internalization under TME promoted decomposition and oxidation. Moreover, these nano-platforms were further decomposed under laser irradiation, which amplified cellular oxidative stress, leading to mitochondrial structural damage and dysfunction, as well as facilitating cuproptosis by interfering with the lipoylated tricarboxylic acid cycle. Cell apoptosis subsequently resulted in significant immunogenic cell death and afforded a versatile nano-transformer for precise imaging-guided bladder cancer therapy.

Fluorinated Iron Metal-Organic Frameworks for Activatable 19F Magnetic Resonance Imaging and Synergistic Therapy of Tumors.

Due to their appealing physiochemical properties, metal-organic frameworks (MOFs) have been widely employed in biomedical fields. In this study, we utilize ferric ions and fluorine-containing organic ligands as both structural and functional units to develop a stimulus-responsive nanoagent, 19FIMOF-TA nanoparticles, for activatable 19F magnetic resonance imaging (MRI) and synergistic therapy of tumors. This nanoagent could respond to excess GSH in a tumor microenvironment, discharging fluorinated organic ligands and reduced ferrous ions. The release of these fluorine-containing small molecules results in boosting of the 19F MRI signals, which could be further enhanced by the photothermal effect of this nanoagent to achieve a responsive cascaded amplification of 19F MRI signals for tumor visualization. Meanwhile, ferroptosis promoted by the ferrous ions leads to significant tumor cell death, which is synergistically aggravated by the photothermal effect. The encouraging results illustrate the promising potential of our nanoagent for effective tumor imaging and combinative cancer therapy.

Protein-Engineered Fibers For Drug Encapsulation Traceable via 19F Magnetic Resonance.

Theranostic materials research is experiencing rapid growth driven by the interest in integrating both therapeutic and diagnostic modalities. These materials offer the unique capability to not only provide treatment but also track the progression of a disease. However, to create an ideal theranostic biomaterial without compromising drug encapsulation, diagnostic imaging must be optimized for improved sensitivity and spatial localization. Herein, we create a protein-engineered fluorinated coiled-coil fiber, Q2TFL, capable of improved sensitivity to 19F magnetic resonance spectroscopy (MRS) detection. Leveraging residue-specific noncanonical amino acid incorporation of trifluoroleucine (TFL) into the coiled-coil, Q2, which self-assembles into nanofibers, we generate Q2TFL. We demonstrate that fluorination results in a greater increase in thermostability and 19F magnetic resonance detection compared to the nonfluorinated parent, Q2. Q2TFL also exhibits linear ratiometric 19F MRS thermoresponsiveness, allowing it to act as a temperature probe. Furthermore, we explore the ability of Q2TFL to encapsulate the anti-inflammatory small molecule, curcumin (CCM), and its impact on the coiled-coil structure. Q2TFL also provides hyposignal contrast in 1H MRI, echogenic signal with high-frequency ultrasound and sensitive detection by 19F MRS in vivo illustrating fluorination of coiled-coils for supramolecular assembly and their use with 1H MRI, 19F MRS and high frequency ultrasound as multimodal theranostic agents.