CuxO decorated Ti3C2Tx MXene composites for non-enzymatic glucose sensing with large linear ranges.

Ti3C2Tx MXene/CuxO composites were prepared by acid etching combined with electrochemical technique. The abundant active sites on the surface of MXene greatly increase the loading of CuxO nanoparticles, and the synergistic effect between the different components of the composite can accelerate the oxidation reaction of glucose. The results indicate that at the working potential of 0.55 V (vs. Ag/AgCl), the glucose sensor based on Ti3C2Tx MXene/CuxO composite presents large linear concentration ranges from 1 µM to 4.655 mM (sensitivity of 361 µA mM-1 cm-2) and from 5.155 mM to 16.155 mM (sensitivity of 133 µA mM-1 cm-2). The limit of detection is 0.065 µM. In addition, the sensor effectively avoids the oxidative interference of common interfering species such as ascorbic acid, dopamine and uric acid. The sensor has good reproducibility, stability and acceptable recoveries for the detection of glucose in human sweat sample (97.5-103.3%) with RSD values less than 4%. Based on these excellent properties it has great potential for the detection of glucose in real samples.

Positron Emission Tomography of Nitric Oxide by a Specific Radical-Generating Dihydropyridine Tracer.

Nitric oxide (NO) plays a pivotal role as a biological signaling molecule, presenting challenges in its specific detection and differentiation from other reactive nitrogen and oxygen species within living organisms. Herein, a 18F-labeled (fluorine-18, t1/2 = 109.7 min) small-molecule tracer dimethyl 4-(4-(4-[18F]fluorobutoxy)benzyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate ([18F]BDHP) is developed based on the dihydropyridine scaffold for positron emission tomography (PET) imaging of NO in vivo. [18F]BDHP exhibits a highly sensitive and efficient C-C cleavage reaction specifically triggered by NO under physiological conditions, leading to the production of a 18F-labeled radical that is readily retained within the cells. High uptakes of [18F]BDHP are found within and around NO-generating cells, such as macrophages treated with lipopolysaccharide or benzo(a)pyrene. MicroPET/CT imaging of arthritic animal model mice reveals distinct tracer accumulation in the arthritic legs, showcasing a higher distribution of NO compared with the control legs. In summary, a specific radical-generating dihydropyridine tracer with a unique radical retention strategy has been established for the marking of NO in real-time in vivo.

Using Biotinylated Iron-Responsive Element to Analyze the Activity of Iron Regulatory Proteins.

Iron regulatory proteins (IRP1 and IRP2) are the master regulators of mammalian iron homeostasis. They bind to the iron-responsive elements (IREs) of the transcripts of iron-related genes to regulate their expression, thereby maintaining cellular iron availability. The primary method to measure the IRE-binding activity of IRPs is the electrophoresis mobility shift assay (EMSA). This method is particularly useful for evaluating IRP1 activity, since IRP1 is a bifunctional enzyme and its protein levels remain similar during conversion between the IRE-binding protein and cytosolic aconitase forms. Here, we exploited a method of using a biotinylated-IRE probe to separate IRE-binding IRPs followed by immunoblotting to analyze the IRE-binding activity. This method allows for the successful measurement of IRP activity in cultured cells and mouse tissues under various iron conditions. By separating IRE-binding IRPs from the rest of the lysates, this method increases the specificity of IRP antibodies and verifies whether a band represents an IRP, thereby revealing some previously unrecognized information about IRPs. With this method, we showed that the S711-phosphorylated IRP1 was found only in the IRE-binding form in PMA-treated Hep3B cells. Second, we found a truncated IRE-binding IRP2 isoform that is generated by proteolytic cleavage on sites in the 73aa insert region of the IRP2 protein. Third, we found that higher levels of SDS, compared to 1-2% SDS in regular loading buffer, could dramatically increase the band intensity of IRPs in immunoblots, especially in HL-60 cells. Fourth, we found that the addition of SDS or LDS to cell lysates activated protein degradation at 37 °C or room temperature, especially in HL-60 cell lysates. As this method is more practical, sensitive, and cost-effective, we believe that its application will enhance future research on iron regulation and metabolism.

An iron-sulfur cluster in the zinc-binding domain of the SARS-CoV-2 helicase modulates its RNA-binding and -unwinding activities.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, uses an RNA-dependent RNA polymerase along with several accessory factors to replicate its genome and transcribe its genes. Nonstructural protein (nsp) 13 is a helicase required for viral replication. Here, we found that nsp13 ligates iron, in addition to zinc, when purified anoxically. Using inductively coupled plasma mass spectrometry, UV-visible absorption, EPR, and Mössbauer spectroscopies, we characterized nsp13 as an iron-sulfur (Fe-S) protein that ligates an Fe4S4 cluster in the treble-clef metal-binding site of its zinc-binding domain. The Fe-S cluster in nsp13 modulates both its binding to the template RNA and its unwinding activity. Exposure of the protein to the stable nitroxide TEMPOL oxidizes and degrades the cluster and drastically diminishes unwinding activity. Thus, optimal function of nsp13 depends on a labile Fe-S cluster that is potentially targetable for COVID-19 treatment.

Vitamin E Induces Liver Iron Depletion and Alters Iron Regulation in Mice.

BACKGROUND: Vitamin E (vit E) is an essential nutrient that functions as a lipophilic antioxidant and is used clinically to treat nonalcoholic fatty liver disease, where it suppresses oxidative damage and impedes the progression of steatosis and fibrosis. Mice lacking a critical liver iron-trafficking protein also manifest steatosis because of iron-mediated oxidative damage and are protected from liver disease by oral vit E supplements. OBJECTIVES: We aimed to examine the role of dietary vit E supplementation in modulating iron-sensing regulatory systems and nonheme iron levels in mouse liver. METHODS: C57Bl/6 male mice, aged 6 wk, were fed purified diets containing normal amounts of iron and either control (45 mg/kg) or elevated (450 mg/kg) levels of 2R-α-tocopherol (vit E) for 18 d. Mouse plasma and liver were analyzed for nonheme iron, levels and activity of iron homeostatic proteins, and markers of oxidative stress. We compared means ± SD for iron and oxidative stress parameters between mice fed the control diet and those fed the vit E diet. RESULTS: The Vit E-fed mice exhibited lower levels of liver nonheme iron (38% reduction, P < 0.0001) and ferritin (74% reduction, P < 0.01) than control-fed mice. The levels of liver mRNA for transferrin receptor 1 and divalent metal transporter 1 were reduced to 42% and 57% of the control, respectively. The mRNA levels for targets of nuclear factor erythroid 2-related factor (Nrf2), a major regulator of the oxidative stress response and iron-responsive genes, were also suppressed in vit E livers. Hepcidin, an iron regulatory hormone, levels were lower in the plasma (P < 0.05), and ferroportin (FPN), the iron exporter regulated by hepcidin, was expressed at higher levels in the liver (P < 0.05). CONCLUSIONS: Oral vit E supplementation in mice can lead to depletion of liver iron stores by suppressing the iron- and redox-sensing transcription factor Nrf2, leading to enhanced iron efflux through liver FPN. Iron depletion may indirectly enhance the antioxidative effects of vit E.

Liquid-Phase Friction of Two-Dimensional Molybdenum Disulfide at the Atomic Scale.

Tribological properties depend strongly on environmental conditions such as temperature, humidity, and operation liquid. However, the origin of the liquid effect on friction remains largely unexplored. Herein, taking molybdenum disulfide (MoS2) as a model system, we explored the nanoscale friction of MoS2 in polar (water) and nonpolar (dodecane) liquids through friction force microscopy. The friction force exhibits a similar layer-dependent behavior in liquids as in air; i.e., thinner samples have a larger friction force. Interestingly, friction is significantly influenced by the polarity of the liquid, and it is larger in polar water than in nonpolar dodecane. Atomically resolved friction images together with atomistic simulations reveal that the polarity of the liquid has a substantial effect on friction behavior, where liquid molecule arrangement and hydrogen-bond formation lead to a higher resistance in polar water in comparison to that in nonpolar dodecane. This work provides insights into the friction on two-dimensional layered materials in liquids and holds great promise for future low-friction technologies.

Effects of Oxide Fragments on Microstructure and Mechanical Properties of AA6061 Aluminum Alloy Tube Fabricated by Thermomechanical Consolidation of Machining Chips.

An AA6061 aluminum alloy tube was fabricated by compacting machining chips via thermomechanical consolidation, including hot pressing and hot extrusion. The microstructure evolution and formation of oxide particles were investigated in correlation to tensile mechanical properties. It was found that fine Al/Mg oxide particles were formed due to the fracture of oxide layers on the chips and the reaction between Mg and Al2O3 during hot extrusion. The oxide particles inhibited the growth of recrystallized α-Al grains, leading to the formation of a microstructure consisting of coarse elongated grains with sizes of 420 µm and fine equiaxed grains with sizes of 10 µm. After T6 heat treatment, a microstructure with finer grains (grain sizes: 34 µm) formed due to further recrystallization induced by residual strain. The tensile mechanical properties testing results indicated that a good combination of strength (296 MPa) and ductility (7.6%) was achieved in the T6 heat treated samples, which were likely attributed to the high-quality inter-chip bonding, as well as the fine oxide particles which were small enough that further crack nucleation and growth around them were inhibited during tensile deformation. For the purpose of comparison, the microstructure and mechanical properties of the as-extruded and T6 heat treated samples produced by hot extrusion of the cast ingot of AA6061 aluminum alloy were also investigated. The lower tensile strength of solid-state recycled tube sample might be associated with the consumption of Mg atoms by the oxidation reaction, leading to the lower density of ß″ precipitates in precipitation strengthening.

In-situ synthesis of NixCo4-xN/N-doped carbon ultrathin nanosheet arrays by supramolecular pyrolysis for boosting electrocatalytic hydrogen evolution in universal pH range water and natural seawater.

Nanostructured electrocatalysts with unique surfaces and interfaces for hydrogen evolution reaction (HER) are crucial for achieving high performance in universal pH water and natural seawater. Herein, a supramolecular liquid precursor was designed and applied to grow NixCo4-xN/N-doped carbon (NC) ultrathin nanosheet arrays (NixCo4-xN/NC) on carbon cloth through one-step pyrolysis. According to the X-ray absorption spectra, Ni was successfully alloyed into Co4N to form NixCo4-xN/NC, which regulates the intrinsic electronic structure and optimizes the adsorption/desorption energy of the catalyst. The unique structure of NixCo4-xN anchored on NC can increase the electron transport efficiency and protect the catalyst from corrosion in the extreme corrosive electrolytes. As a result, the NixCo4-xN/NC catalyst exhibits excellent electrocatalytic HER activity over a wide pH range requiring only 46, 75, and 55 mV at 10 mA/cm2 in the acidic, neutral, and alkaline electrolytes, respectively. Interestingly, the catalyst also shows outstanding HER performance in the natural seawater. This work provides an alternative option for the rational design of efficient electrocatalysts for universal pH water/seawater splitting.

Surface engineering of carbon-coated cobalt-doped nickel phosphides bifunctional electrocatalyst for boosting 5-hydroxymethylfurfural oxidation coupled with hydrogen evolution.

Multiple surface/interface engineering is an effective approach to develop efficient electrocatalysts for promoting the practical application of electrocatalysis and achieving carbon neutrality. Herein, a deep eutectic liquid precursor containing phosphorus was designed. The self-supported three-dimensional (3D) cobalt-doped Ni12P5/Ni3P nanowire networks coated with a thin layer of carbon (Co-NixP@C) were prepared by using an in-situ one-step pyrolysis method. The as-obtained Co-NixP@C hybrid possesses a superaerophobic/superhydrophilic surface, which could promote electrolyte diffusion and enhance bubble release. Density functional theory (DFT) calculations reveal that Co-doping in NixP@C can promote the adsorption and activation of 5-hydroxymethylfurfural (HMF) molecules, and optimize the energy barrier of H* absorption. The self-supported Co-NixP@C was used as an efficient bifunctional electrocatalyst for HMF oxidation coupled with hydrogen evolution reaction (HER) in a 1.0 M KOH solution. A nearly 100 % yield of 2,5-furandicarboxylic acid (FDCA) was achieved. The self-supported Co-NixP@C displayed high activity and stability for both HER and HMF conversion. The HMF oxidation coupled with HER can be efficiently driven by a 1.5 V commercial photovoltaic panel under sunlight. This study lays the foundation for large-scale industrialization in sustainable fine-chemical and energy engineering.

A novel 18F-labeled agonist for PET imaging of stimulator of interferon gene expression in tumor-bearing mice.

PURPOSE: Stimulator of interferon genes (STING) protein plays a vital role in the immune surveillance of tumor microenvironment. Monitoring STING expression in tumors benefits the relevant STING therapy. This study aimed to develop a novel 18F-labeled agonist, dimeric amidobenzimidazole (diABZI), and firstly evaluate the feasibility of noninvasive positron emission tomography (PET) imaging of STING expression in the tumor microenvironment. METHODS: An analog of the STING agonist NOTA-DABI was synthesized and labeled with 18F via Al18F-NOTA complexation (denoted as [18F]F-DABI). Physicochemical properties, STING protein-binding affinity, and specificity of [18F]F-DABI were evaluated using cell uptake and docking assays. In vivo small-animal PET imaging and biodistribution studies of [18F]F-DABI in tumor-bearing mice were performed to verify the pharmacokinetics and tumor targeting ability. The correlation between tumor uptake and STING expression was also analyzed. RESULTS: [18F]F-DABI was produced conveniently with high radiochemical yield (44 ± 15%), radiochemical purity (> 97%) and molar activity (15-30 GBq/µmol). In vitro binding assays demonstrated that [18F]F-DABI has a favorable affinity and specificity for STING with a KD of 12.98 ± 2.07 nM. In vivo studies demonstrated the specificity of [18F]F-DABI for PET imaging of STING expression with B16F10 tumor uptake of 10.93 ± 0.93%ID/g, which was significantly different from that of blocking groups (3.13 ± 0.88%ID/g, ***p < 0.0001). Furthermore, tumor uptake of [18F]F-DABI was well positively correlated with STING expression in different tumor types. Biodistribution results demonstrated that [18F]F-DABI was predominately uptaken in the liver and intestines, indicating its hepatobiliary elimination. CONCLUSION: This proof-of-concept study demonstrated a STING-binding radioligand for PET imaging, which could be used as a potential companion diagnostic tool for related STING-agonist therapies.

Development of a novel radiofluorinated riboflavin probe for riboflavin receptor-targeting PET imaging.

Riboflavin receptor 3 (RFVT3) is a key protein in energetic metabolism reprogramming and is overexpressed in multiple cancers involved in malignant proliferation, angiogenesis, chemotherapy resistance, and immunosuppression. To enable non-invasive real-time quantification of RFVT3 in tumors, we sought to develop a suitable PET probe that would allow specific and selective RFVT3 imaging in vivo. A novel radiofluorinated riboflavin probe (18F-RFTA) based on riboflavin was synthesized and characterized in terms of radiochemical purity, hydrophilicity, binding affinity, and stability. Positron emission tomography (PET) imaging of 18F-RFTA was performed in U87MG tumor-bearing mice. Immunohistochemistry staining was carried out to determine the expression of RFVT3 in U87MG tumors. 18F-RFTA was characterized by high radiochemical purity and RFVT3 binding affinity, and remarkable stability in vitro and in vivo. Small-animal PET imaging with 18F-RFTA revealed significantly higher uptake in RFVT3-expressing U87MG tumors than in muscle. In conclusion, we have developed the first radiofluorinated riboflavin-based PET probe that is suitable for imaging RFVT3-positive tumors. The new target/probe system can be leveraged for extensive use in the diagnosis and treatment of RFVT3 overexpressing diseases, such as oncologic, cardiovascular, and neurodegenerative diseases.

Design, Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents.

In this study, a series of 4-[(quinolin-4-yl)amino]benzamide derivatives as the novel anti-influenza agents were designed and synthesized. Cytotoxicity assay, cytopathic effect assay and plaque inhibition assay were performed to evaluate the anti-influenza virus A/WSN/33 (H1N1) activity of the target compounds. The target compound G07 demonstrated significant anti-influenza virus A/WSN/33 (H1N1) activity both in cytopathic effect assay (EC50 = 11.38 ± 1.89 µM) and plaque inhibition assay (IC50 = 0.23 ± 0.15 µM). G07 also exhibited significant anti-influenza virus activities against other three different influenza virus strains A/PR/8 (H1N1), A/HK/68 (H3N2) and influenza B virus. According to the result of ribonucleoprotein reconstitution assay, G07 could interact well with ribonucleoprotein with an inhibition rate of 80.65% at 100 µM. Furthermore, G07 exhibited significant activity target PA-PB1 subunit of RNA polymerase according to the PA-PB1 inhibitory activity prediction by the best pharmacophore Hypo1. In addition, G07 was well drug-likeness based on the results of Lipinski's rule and ADMET prediction. All the results proved that 4-[(quinolin-4-yl)amino]benzamide derivatives could generate potential candidates in discovery of anti-influenza virus agents.

Ultrathin and Porous 2D PtPdCu Nanoalloys as High-Performance Multifunctional Electrocatalysts for Various Alcohol Oxidation Reactions.

We precisely synthesized two-dimensional (2D) PtPdCu nanostructures with the morphology varying from porous circular nanodisks (CNDs) and triangular nanoplates (TNPs) to triangular nanoboomerangs (TNBs) by tuning the molar ratios of metal precursors. The PtPdCu trimetallic nanoalloys exhibit superior electrocatalytic performances to alcohol oxidation reactions due to their unique structural features and the synergistic effect. Impressively, PtPdCu TNBs exhibit a high mass activity of 3.42 mgPt+Pd-1 and 1.06 A·mgPt-1 for ethanol and methanol oxidation compared to PtPd, PtCu, and pure Pt, which is 3.93 and 4.07 times that of commercial Pt/C catalysts, respectively. Moreover, 2D PtPdCu TNPs and PtPdCu CNDs also show a highly improved electrocatalytic activity. Furthermore, as all-in-one electrocatalysts, PtPdCu nanoalloys display excellent electrocatalytic activity and stability toward the oxidation of other alcohol molecules, such as isopropyl alcohol, glycerol, and ethylene glycol. The enhanced mechanism was well proposed to be the abundant active sites and upshifted d-band center based on density functional theory calculations.

Micro-SPECT Imaging of Acute Ischemic Stroke with Radioiodinated Riboflavin in Rat MCAO Models via Riboflavin Transporter Targeting.

Riboflavin transporter-3 (RFVT3) is a recently discovered and novel biomarker for the theranostics of nervous system diseases. RFVT3 is significantly overexpressed in cerebral injury after ischemic stroke. Herein, we first reported an RFVT3-targeted tracer 131I-riboflavin (131I-RFLA) for SPECT imaging of ischemic stroke in vivo. 131I-RFLA was radiosynthesized by the iodogen-coating method. 131I-RFLA possessed a radiochemical yield of 69.2 ± 3.7% and greater than 95% radiochemical purity. The representative SPECT/CT images using 131I-RFLA demonstrated the conspicuously increased tracer uptake in the cerebral injury by comparison with the contralateral normal brain at 1 h and 3 and 7 d after stroke. Ex vivo autoradiography demonstrated that the ratio of infarcted to normal brain uptake was 3.63 and it was decreased to 1.98 after blocking, which reconfirmed the results of SPECT images. Importantly, a significant correlation was identified between RFVT3 expression and brain injury by H&E and immunohistochemistry staining. Therefore, RFVT3 is a new and potential biomarker for the early diagnosis of ischemic stroke. In addition, 131I-RFLA is a promising SPECT tracer for imaging RFVT3-related ischemic cerebral injury in vivo.

Investigation of Microstructures and Mechanical Properties of SiC/AA2024 Nanocomposites Processed by Powder Metallurgy and T6 Heat Treatment.

SiC/AA2024 nanocomposites with 1 and 5 vol.% SiC nanoparticles have been prepared by a powder metallurgy route involving high-energy ball-milling (HEBM), spark plasma sintering (SPS), and hot extrusion. The microstructures and mechanical properties of the nanocomposite samples before and after T6 heat treatment were investigated. The samples exhibited a bimodal microstructure with SiC nanoparticles being dispersed in it. With increasing the SiC nanoparticle content from 1 to 5 vol.%, the yield strength (YS) and ultimate tensile strength (UTS) increased and the elongation to fracture (El) slightly decreased. After T6 heat treatment, a simultaneous improvement of the strength and ductility was observed, with the YS, UTS, and El increasing from 413 MPa, 501 MPa, and 5.4% to 496 MPa, 572 MPa, and 6.7%, respectively, in the 1 vol.%SiC/AA2024 nanocomposite sample. Analysis of the deformation behavior shows that this improvement is likely caused by the increased density of geometrically necessary dislocations (GNDs) resulting from the bimodal microstructure. The dispersed intragranular S' precipitates generated by the T6 heat treatment also make a contribution to the increase of strength and ductility by accumulating dislocations. It is feasible to realize simultaneous improvement of strength and ductility in the SiC/AA2024 nanocomposites via powder metallurgy and subsequent heat treatment.

A Paradigm of Cancer Immunotherapy Based on 2-[18F]FDG and Anti-PD-L1 mAb Combination to Enhance the Antitumor Effect.

PURPOSE: Efforts have been devoted to select eligible candidates for PD-1/PD-L1 immune checkpoint blocker (ICB) immunotherapy. Here, we have a serendipitous finding of positron emission tomography (PET) imaging tracer 2-[18F]FDG as a potential immunomodulator. Therefore, we hypothesize that 2-[18F]FDG could induce PD-L1 expression change and create an immune-favorable microenvironment for tumor immunotherapy. EXPERIMENTAL DESIGN: We designed a series of assays to verify PD-L1 upregulation, and tested immunotherapy regimens based on 2-[18F]FDG and anti-PD-L1 mAb, as monotherapy and in combination, in fully immunocompetent mice of MC38 and CT26 models. PD-L1 expression and tumor microenvironment (TME) changes were analyzed by Western blot, transcriptomics study, and flow-cytometric analysis. RESULTS: PD-L1 was upregulated in a time- and dose-dependent manner after being induced by 2-[18F]FDG. The activation of NF-κB/IRF3 pathway and STAT1/3-IRF1 pathway play crucial parts in modulating PD-L1 expression after DNA damage and repair. Improved αPD-L1 mAb utilization rate and significant tumor growth delay were observed when the personalized therapeutic alliance of 2-[18F]FDG stimulation and ICB was used. In addition, combination of 2-[18F]FDG with αPD-L1 mAb could reprogram a TME from "cold" to "hot," to make low immunoactivity tumors sensitive to ICB therapy. CONCLUSIONS: In summary, this promising paradigm has the potential to expand the traditional tumor theranostics. 2-[18F]FDG-based ICB immunotherapy is highly significant in enhancing antitumor effect. A research of 2-[18F]FDG-based ICB immunotherapy has been proposed to enhance the antitumor effect.

Probing the hydration friction of ionic interfaces at the atomic scale.

Despite the extensive studies conducted in exploring friction in the aqueous environment, the mechanism of hydration friction remains not well understood. Herein, we directly probed hydration friction on mica-electrolyte interfaces with different hydrated alkali cations through a combination of three-dimensional atomic force microscopy and friction force microscopy. The atomic scale imaging of the hydration layers at the mica surface in different electrolyte solutions clearly revealed a correlation between the alkali cations and the structure of the hydration layers. Our detailed analysis showed that the hydration force was much higher at high ionic concentrations than that at low concentrations. The hydration friction coefficient was found to follow the trend K+< Na+< Li+< Cs+, which contrasts with the Hofmeister series, indicating that the hydration friction depends not only on the hydration strength of the alkali cations but also on the arrangement of the alkali cations at the interface. The results of this study provide deep insights into the origins of hydration friction, with potential implications for the development of new boundary lubrication in aqueous media.

Enantioselective Deaminative Alkylation of Amino Acid Derivatives with Unactivated Olefins.

Herein, we report the first Ni-catalyzed enantioselective deaminative alkylation of amino acid and peptide derivatives with unactivated olefins. Key for success was the discovery of a new sterically encumbered bis(oxazoline) ligand backbone, thus offering a de novo technology for accessing enantioenriched sp3-sp3 linkages via sp3 C-N functionalization. Our protocol is distinguished by its broad scope and generality across a wide number of counterparts, even in the context of late-stage functionalization. In addition, an enantioselective deaminative remote hydroalkylation reaction of unactivated internal olefins is within reach, thus providing a useful entry point for forging enantioenriched sp3-sp3 centers at remote sp3 C-H sites.

MicroSPECT Imaging-Guided Treatment of Idiopathic Pulmonary Fibrosis in Mice with a Vimentin-Targeting 99mTc-Labeled N-Acetylglucosamine-Polyethyleneimine.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease with poor prognosis. Evidence has shown that vimentin is a key regulator of lung fibrogenesis. 99mTc-labeled N-acetylglucosamine-polyethyleneimine (NAG-PEI), a vimentin-targeting radiotracer, was used for the early diagnosis of IPF, and NAG-PEI was also used as a therapeutic small interfering RNA (siRNA) delivery vector for the treatment of IPF in this study. Single-photon emission-computed tomography (SPECT) imaging of bleomycin (BM)- and silica-induced IPF mice with 99mTc-labeled NAG-PEI was performed to visualize pulmonary fibrosis and monitor the treatment efficiency of siRNA-loaded NAG-PEI, lipopolysaccharide (LPS, a tolerogenic adjuvant), or zymosan (ZYM, an immunostimulant). The lung uptakes of 99mTc-NAG-PEI in the BM- and silica-induced IPF mice were clearly and directly correlated with IPF progression. The lung uptake of 99mTc-NAG-PEI in the NAG-PEI/TGF-ß1-siRNA treatment group or LPS treatment group was evidently lower than that in the control group, while the lung uptake of 99mTc-NAG-PEI was significantly higher in the ZYM treatment group compared to that in the control group. These results demonstrate that NAG-PEI is a potent MicroSPECT imaging-guided theranostic platform for IPF diagnosis and therapy.

Development and Preclinical Evaluation of Radiolabeled Covalent G12C-Specific Inhibitors for Direct Imaging of the Oncogenic KRAS Mutant.

Although KRAS has been an important target for many cancers, direct inhibition of oncogenic RAS remains challenging. Until recently, covalent KRAS G12C-specific inhibitors have been developed and progressed to the clinics. Nevertheless, not all patients benefit from these covalent inhibitors. At present, identification of candidates for this treatment requires tissue biopsies and gene sequencing, which are invasive, time-consuming, and could be of insufficient quality and limited predictive value owing to tumor heterogeneity. The use of noninvasive molecular imaging techniques such as PET and SPECT for spying KRAS G12C mutation in tumors provide a promising strategy for circumventing these hurdles. In the present study, based on the covalent G12C-specific inhibitor ARS-1620, we sought to develop radiolabeled small molecules for direct imaging of the KRAS mutation status in tumors. [131I]I-ARS-1620 and [18F]F-ARS-1620 were successfully prepared with high radiochemical yield, radiochemical purity, and molar activity. In vitro and in vivo studies have demonstrated the affinity, specificity, and capacity of [131I]I-ARS-1620 for direct imaging of the oncogenic KRAS G12C mutant. This initial attempt allows us to directly screen the KRAS G12C mutant for the first time in vivo.