Expression of concern: Gadolinium embedded iron oxide nanoclusters as T1-T2 dual-modal MRI-visible vectors for safe and efficient siRNA delivery.

Expression of concern for 'Gadolinium embedded iron oxide nanoclusters as T1-T2 dual-modal MRI-visible vectors for safe and efficient siRNA delivery' by Xiaoyong Wang et al., Nanoscale, 2013, 5, 8098-8104, https://doi.org/10.1039/C3NR02797J.

Two-Level Self-Thickening Mechanism of a Novel Acid Thickener with a Hydrophobic-Associated Structure during High-Temperature Acidification Processes.

Two acid thickeners, ADMC and ADOM, were prepared by aqueous solution polymerization using acrylamide (AM) and methacryloyloxyethyl trimethyl ammonium chloride (DMC) as raw materials, with or without the introduction of octadecyl polyoxyethylene ether methacrylate (OEMA). It was characterized by FTIR, 1H NMR, and the fluorescence spectra of pyrene. The double-layer thickening mechanism of ADOM was proved by comparing the thickening and rheological properties of ADMC and ADOM tested by a six-speed rotary viscometer and a HAKKE MARSIV rheometer during the acidification process. The results showed that the synthetic product was the target product; the first stage of the self-thickening ADOM fresh acid solution during high-temperature acidification was mainly affected by Ca2+ concentration, and the second stage of self-thickening was mainly affected by temperature. The residual viscosity of the 0.8 wt% ADOM residual acid solution was 250, 201.5, and 61.3 mPa·s, respectively, after shearing at 90, 120, and 150 °C for 60 min at a shear rate of 170 s-1. The thickening acid ADOM with a hydrophobic association structure has good temperature resistance and shear resistance, which can be used for high-temperature deep-well acid fracturing. In addition, no metal crosslinking agent was introduced in the system to avoid damage to its formation, and ADOM exhibited good resistance to Ca2+, which could provide ideas for the reinjection of the acidizing flowback fluid. It also has certain advantages for environmental protection.

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.

Glycan Metabolic Fluorine Labeling for In Vivo Visualization of Tumor Cells and In Situ Assessment of Glycosylation Variations.

The abnormality in the glycosylation of surface proteins is critical for the growth and metastasis of tumors and their capacity for immunosuppression and drug resistance. This anomaly offers an entry point for real-time analysis on glycosylation fluctuations. In this study, we report a strategy, glycan metabolic fluorine labeling (MEFLA), for selectively tagging glycans of tumor cells. As a proof of concept, we synthesized two fluorinated unnatural monosaccharides with distinctive 19 F chemical shifts (Ac4 ManNTfe and Ac4 GalNTfa). These two probes could undergo selective uptake by tumor cells and subsequent incorporation into surface glycans. This approach enables efficient and specific 19 F labeling of tumor cells, which permits in vivo tracking of tumor cells and in situ assessment of glycosylation changes by 19 F MRI. The efficiency and specificity of our probes for labeling tumor cells were verified in vitro with A549 cells. The feasibility of our method was further validated with in vivo experiments on A549 tumor-bearing mice. Moreover, the capacity of our approach for assessing glycosylation changes of tumor cells was illustrated both in vitro and in vivo. Our studies provide a promising means for visualizing tumor cells in vivo and assessing their glycosylation variations in situ through targeted multiplexed 19 F MRI.

Fe(II)-Targeted PET/19F MRI Dual-Modal Molecular Imaging Probe for Early Evaluation of Anticancer Drug-Induced Acute Kidney Injury.

Ferroptosis, an iron-dependent regulated cell death, has been emerging as an early mechanism in anticancer drug-induced acute kidney injury (AKI) that may benefit therapeutic intervention. However, the lack of molecular imaging methods for in vivo detection of ferroptosis restricts the early diagnosis of anticancer drug-induced AKI. Herein, we developed a PET/19F MRI dual-modal imaging probe for the monitoring of ferroptosis in AKI by chemically conjugating the Fe(II)-sensitive artemisinin (Art) motif and macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to the CF3-modified polyhedral oligomeric silsesquioxane (POSS) clusters, denoted as the PAD probe. The PAD probe could be converted into PA*D in the presence of Fe(II) ions and subsequently be intercepted by biological macromolecules nearby, thereby enhancing the retention effect in ferroptotic cells and tissues. After labeling with 68Ga isotopes, the 68Ga-labeled PAD probe in cisplatin (CDDP)-induced AKI mice displayed a significantly higher renal uptake level than that in normal mice. Moreover, the PAD probe with a precise chemical structure, relatively high 19F content, and single 19F resonance frequency allowed for interference-free and high-performance19F MRI that could detect the onset of CDDP-induced AKI at least 24 h earlier than the typical clinical/preclinical assays. Our study provides a robust dual-modal molecular imaging tool for the early diagnosis and mechanistic investigation of various ferroptosis-related diseases.

Macrophage Reprogramming via Targeted ROS Scavenging and COX-2 Downregulation for Alleviating Inflammation.

Inflammation-related diseases affect large populations of people in the world and cause substantial healthcare burdens, which results in significant costs in time, material, and labor. Preventing or relieving uncontrolled inflammation is critical for the treatment of these diseases. Herein, we report a new strategy for alleviating inflammation by macrophage reprogramming via targeted reactive oxygen species (ROS) scavenging and cyclooxygenase-2 (COX-2) downregulation. As a proof of concept, we synthesize a multifunctional compound named MCI containing a mannose-based macrophage targeting moiety, an indomethacin (IMC)-based segment for inhibiting COX-2, and a caffeic acid (CAF)-based section for ROS clearance. As revealed by a series of in vitro experiments, MCI could significantly attenuate the expression of COX-2 and the level of ROS, leading to M1 to M2 macrophage reprogramming, as evidenced by the reduction and the elevation in the levels of pro-inflammatory M1 markers and anti-inflammatory M2 markers, respectively. Furthermore, in vivo experiments show MCI's promising therapeutic effects on rheumatoid arthritis (RA). Our work illustrates the success of targeted macrophage reprogramming for inflammation alleviation, which sheds light on the development of new anti-inflammatory drugs.

Constructing sequence-controlled heterolayered dendritic lanthanide chelates via a one-pot strategy using orthogonal chemistry.

The construction of sequence-controlled heterometallic lanthanide complexes is challenging despite their intriguing physical/chemical properties and enormous potential applications. Here we report a one-pot strategy that exploits orthogonal chemical reactions for modular assembly, which allows for rapid preparation of sequence-controlled heterolayered lanthanide-complex dendritic structures.

Water-Soluble Chemically Precise Fluorinated Molecular Clusters for Interference-Free Multiplex 19F MRI in Living Mice.

Fluorine-19 magnetic resonance imaging (19F MRI) is gaining widespread interest from the fields of biomolecule detection, cell tracking, and diagnosis, benefiting from its negligible background, deep tissue penetration, and multispectral capacity. However, a wide range of 19F MRI probes are in great demand for the development of multispectral 19F MRI due to the limited number of high-performance 19F MRI probes. Herein, we report a type of water-soluble molecular 19F MRI nanoprobe by conjugating fluorine-containing moieties with a polyhedral oligomeric silsesquioxane (POSS) cluster for multispectral color-coded 19F MRI. These chemically precise fluorinated molecular clusters are of excellent aqueous solubility with relatively high 19F contents and of single 19F resonance frequency with suitable longitudinal and transverse relaxation times for high-performance 19F MRI. We construct three POSS-based molecular nanoprobes with distinct 19F chemical shifts at -71.91, -123.23, and -60.18 ppm and achieve interference-free multispectral color-coded 19F MRI of labeled cells in vitro and in vivo. Moreover, in vivo 19F MRI reveals that these molecular nanoprobes could selectively accumulate in tumors and undergo rapid renal clearance afterward, illustrating their favorable in vivo behavior for biomedical applications. This study provides an efficient strategy to expand the 19F probe libraries for multispectral 19F MRI in biomedical research.

Metabolic fluorine labeling and hotspot imaging of dynamic gut microbiota in mice.

Real-time localization and microbial activity information of indigenous gut microbiota over an extended period of time remains a challenge with existing visualizing methods. Here, we report a metabolic fluorine labeling (MEFLA)-based strategy for monitoring the dynamic gut microbiota via 19F magnetic resonance imaging (19F MRI). In situ labeling of different microbiota subgroups is achieved by using a panel of peptidoglycan-targeting MEFLA probes containing 19F atoms of different chemical shifts, and subsequent real-time in vivo imaging is accomplished by multiplexed hotspot 19F MRI with high sensitivity and unlimited penetration. Using this method, we realize extended visualization (>24 hours) of native gut microbes located at different intestinal sections and semiquantitative analysis of their metabolic dynamics modulated by various conditions, such as the host death and different ß-lactam antibiotics. Our strategy holds great potential for noninvasive and real-time assessing of the metabolic activities and locations of the highly dynamic gut microbiota.

Targeting the activity of T cells by membrane surface redox regulation for cancer theranostics.

T cells play a determining role in the immunomodulation and prognostic evaluation of cancer treatments relying on immune activation. While specific biomarkers determine the population and distribution of T cells in tumours, the in situ activity of T cells is less studied. Here we designed T-cell-targeting fusogenic liposomes to regulate and quantify the activity of T cells by exploiting their surface redox status as a chemical target. The T-cell-targeting fusogenic liposomes equipped with 2,2,6,6-tetramethylpiperidine (TEMP) groups neutralize reactive oxygen species protecting T cells from oxidation-induced loss of activity. Meanwhile, the production of paramagnetic 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) radicals allows magnetic resonance imaging quantification of the T cell activity. In multiple mouse models, the T-cell-targeting fusogenic liposomes led to efficient tumour inhibition and to early prediction of radiotherapy outcomes. This study uses a chemical targeting strategy to measure the in situ activity of T cells for cancer theranostics and may provide further understanding on engineering T cells for cancer treatment.

Bio-orthogonal Metabolic Fluorine Labeling Enables Deep-Tissue Visualization of Tumor Cells In Vivo by 19F Magnetic Resonance Imaging.

The high resolution, deep penetration, and negligible biological background of 19F magnetic resonance imaging (MRI) makes it a potential means for imaging various biological targets in vivo. However, the limited targeting strategies of current 19F MRI probes significantly restrict their applications for in vivo tracking of low-abundance targets and specific biological processes, which greatly stimulates the investigations on new targeting methods for 19F MRI. Herein, we report a strategy, termed as bio-orthogonal metabolic fluorine labeling, for selective cellular 19F labeling, which permits in vivo imaging of tumor cells with high specificity. This strategy exploits the display of azido groups on the cell surface via selective uptake and metabolic engineering of tetra-acetylated N-azidoacetylmannosamine (Ac4ManAz) by cancer cells and subsequent rapid and specific bio-orthogonal ligation between azido and cyclootynyl groups to incorporate 19F-containing moieties on the surface of cancer cells. We validated the feasibility of this method on the cellular level with A549 and HepG2 cells and further illustrated the application of this method for in vivo deep-tissue visualization of cancer cells with A549 tumor-bearing BALB/c mice using hot spot 19F MRI. Our strategy expands the arsenal for targeted 19F MRI and provides a promising method for imaging biological targets in living subjects with high tissue penetration and low biological background.

19 F Barcoding Enables Multiplex Detection of Biomarkers Associated with Organ Injury and Cancer.

Simultaneous detection of multiple biomarkers in complex environments is critical for the in-depth exploration of different biological processes, which is challenging for many current analytical methods due to various limitations. Herein, we report a strategy of 19 F barcoding which takes the advantages of 19 F's high magnetic resonance (MR) sensitivity, prompt signal response to environmental changes, negligible biological background, quantitative signal output, and multiplex capacity. A set of 19 F-barcoded sensors responding to different biomarkers involved in organ injury and cancer are designed, synthesized, and characterized. With these sensors, we accomplish concurrent assessment of different biomarkers in the samples collected from the mice with drug-induced liver/kidney injury or tumor, illustrating the feasibility of this approach for multiplexed detection of different biomarkers in complex environments during various biological processes.

A dual-responsive doxorubicin-indoximod conjugate for programmed chemoimmunotherapy.

Herein we report a dual-responsive doxorubicin-indoximod conjugate (DOXIND) for programmed chemoimmunotherapy. This conjugate is able to release doxorubicin and indoximod upon exposure to appropriate stimuli for synergistic chemotherapy and immunotherapy, respectively. We demonstrate its promoting effects on immune response and inhibiting effects on tumor growth through a series of in vitro and in vivo experiments.

An Activatable 19 F MRI Molecular Probe for Sensing and Imaging of Norepinephrine.

Norepinephrine (NE), acting as both a neurotransmitter and hormone, plays a significant role in regulating the action of the brain and body. Many studies have demonstrated a strong correlation between mental disorders and aberrant NE levels. Therefore, it is of urgent demand to develop in vivo analytical methods of NE for diagnostic assessment and mechanistic investigations of mental diseases. Herein, we report a 19 F MRI probe (NRFP) for sensing and imaging NE, which is constructed by conjugating a gadolinium chelate to a fluorine-containing moiety through a NE-responsive aromatic thiocarbonate linkage. The capacity and specificity of NRFP for detecting NE is validated with in vitro detecting/imaging experiments. Furthermore, the feasibility of NRFP for visualizing NE in animals is illustrated by ex vivo and in vivo imaging experiments, demonstrating the promising potential of NRFP for selective detection and specific imaging of NE in deep tissues of living subjects.

Photoinduced Superhydrophilicity of Gd-Doped TiO2 Ellipsoidal Nanoparticles Boosts T1 Contrast Enhancement for Magnetic Resonance Imaging.

The unsatisfactory performance of current gadolinium chelate based T1 contrast agents (CAs) for magnetic resonance imaging (MRI) stimulates the search for better alternatives. Herein, we report a new strategy to substantially improve the capacity of nanoparticle-based T1 CAs by exploiting the photoinduced superhydrophilic assistance (PISA) effect. As a proof of concept, we synthesized citrate-coated Gd-doped TiO2 ellipsoidal nanoparticles (GdTi-SC NPs), whose r1 increases significantly upon UV irradiation. The reduced water contact angle and the increased number of surface hydroxyl groups substantiate the existence of the PISA effect, which considerably promotes the efficiency of paramagnetic relaxation enhancement (PRE) and thus the imaging performance of GdTi-SC NPs. In vivo MRI of SD rats with GdTi-SC NPs further demonstrates that GdTi-SC NPs could serve as a high-performance CA for sensitive imaging of blood vessels and accurate diagnosis of vascular lesions, indicating the success of our strategy.

Tandem Chemoimmunotherapy by a Cascade-Responsive Molecular Prodrug.

The limited therapeutic effects of immunotherapy for most types of cancer stimulates the pursuit for efficient methods to improve its response rate. Herein we report the design and synthesis of a cascade-responsive molecular prodrug for tandem chemoimmunotherapy. This molecular prodrug first releases doxorubicin (DOX) in the mildly acidic tumor microenvironment (TME) to induce immunogenic cell death (ICD) of tumor cells. Caspase 3/7 released during tumor cell apoptosis liberates NLG919 from the prodrug, which inhibits the activity of indoleamine 2,3-dioxygenase (IDO) and results in relief of TME immunosuppression. Meanwhile, tumor-associated antigens and immune stimulatory cytokines released during ICD activate the immune response against the tumor, leading to synergistic chemoimmunotherapy. The efficacy of this prodrug is validated by in vitro and in vivo experiments, demonstrating the success of this strategy for cancer treatment.