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.

A deep learning based method for automatic analysis of high-throughput droplet digital PCR images.

Droplet digital PCR (ddPCR) is a technique for absolute quantification of nucleic acid molecules and is widely used in biomedical research and clinical diagnosis. ddPCR partitions the reaction solution containing target molecules into a large number of independent microdroplets for amplification and performs quantitative analysis of target molecules by calculating the proportion of positive droplets by the principle of Poisson distribution. Accurate recognition of positive droplets in ddPCR images is of great importance to guarantee the accuracy of target nucleic acid quantitative analysis. However, hand-designed operators are sensitive to interference and have disadvantages such as low contrast, uneven illumination, low sample copy number, and noise, and their accuracy and robustness still need to be improved. Herein, we developed a deep learning-based high-throughput ddPCR droplet detection framework for robust and accurate ddPCR image analysis, and the experimental results show that our method achieves excellent performance in the recognition of positive droplets (99.71%) within a limited time. By combining the Hough transform and a convolutional neural network (CNN), our novel method can automatically filter out invalid droplets that are difficult to be identified by local or global encoding methods and realize high-precision localization and classification of droplets in ddPCR images under variable exposure, contrast, and uneven illumination conditions without the need for image pre-processing and normalization processes.

Synergism of 64Cu-Labeled RGD with Anti-PD-L1 Immunotherapy for the Long-Acting Antitumor Effect.

We put forward a novel targeting-triggering-therapy (TTT) scheme that combines 64Cu-based targeted radionuclide therapy (TRT) with programmed death-ligand 1 (PD-L1)-based immunotherapy for enhancing therapeutic efficacy. The αvß3 integrin-targeted 64Cu-DOTA-EB-cRGDfK (64Cu-DER) was synthesized. Flow cytometry, immunofluorescence staining, and RT-qPCR were performed to verify PD-L1 upregulation after irradiation with 64Cu-DER. Positron emission tomography imaging was performed to investigate the prominent tumor retention property of 64Cu-DER. In the MC38 tumor model, anti-PD-L1 antibody (αPD-L1 mAb) was delivered in a concurrent or sequential manner after 64Cu-DER was injected, followed by the testing of changes in tumor microenvironment (TME). PD-L1 was upregulated in a time- and dose-dependent manner after being induced by 64Cu-DER. The combination of 64Cu-DER TRT (925 MBq/kg) and αPD-L1 mAb (10 mg/kg) resulted in significant delay in tumor growth and protected against tumor rechallenge. Blockade of PD-L1 at 4 h after 64Cu-DER TRT (64Cu-DER + αPD-L1 mAb @ 4 h combination group) was able to achieve 100% survival rate, prevent tumor relapse, and evidently prolong the survival of mice. In summary, the combination of 64Cu-DER and αPD-L1 mAb in a time-dependent manner could be a promising approach to improve therapeutic efficacy. Understandably, this strategy has the potential to extend the scope of 64Cu-based TTT and merits translation into clinical practice for the better management of immune checkpoint blockade immunotherapy.

A radioiodinated FR-ß-targeted tracer with improved pharmacokinetics through modification with an albumin binder for imaging of macrophages in AS and NAFL.

PURPOSE: The formation of advanced plaques, which is characterized by the uninterrupted aggregation of macrophages with high expression of folate receptor-ß (FR-ß), is observed in several concomitant metabolic syndromes. The objective of this study was to develop a novel FR-ß-targeted single-photon emission computed tomography (SPECT) radiotracer and validate its application to the noninvasive detection of atherosclerosis (AS) plaque and non-alcoholic fatty liver (NAFL). METHODS: Two radioiodinated probes, [131I]IPBF and [131I]IBF, were developed, and cell uptake studies were used to identify their specific targets for activated macrophages. Biodistribution in normal mice was performed to obtain the pharmacokinetic information of the probes. Apolipoprotein E knockout (ApoE-/-) mice with atherosclerotic aortas were induced by a high-fat and high-cholesterol (HFHC) diet. To investigate the affinity of radiotracers to FR-ß, Kd values were determined using in vitro assays. In addition, the assessments of the aorta in the ApoE-/- mice at different stages were performed using in vivo SPECT/CT imaging, and the findings were compared by histology. RESULTS: Both [131I]IPBF and [131I]IBF were synthesized with > 95% radiochemical purity and up to 3 MBq/nmol molar activity. In vitro assay of [131I]IPBF showed a moderate binding affinity to plasma proteins and specific uptake in activated macrophages. The prolonged blood elimination half-life (t1/2z) of [131I]IPBF (8.14 h) was observed in a pharmacokinetic study of normal mice, which was significantly longer than that of [131I]IBF (t1/2z = 2.95 h). As expected, the Kd values of [131I]IPBF and [131I]IBF in the Raw 264.7 cells were 43.94 ± 9.83 nM and 61.69 ± 15.19 nM, respectively. SPECT imaging with [131I]IPBF showed a high uptake in advanced plaques and NAFL. Radioactivity in excised aortas examined by ex vivo autoradiography further confirmed the specific uptake of [131I]IPBF in high-risk AS plaques. CONCLUSIONS: In summary, we reported a proof-of-concept study of an albumin-binding folate derivative for macrophage imaging. The FR-ß-targeted probe, [131I]IPBF, significantly prolongs the plasma elimination half-life and has the potential for the monitoring of AS plaques and concomitant fatty liver.

Coordinating the Mechanisms of Action of Ferroptosis and the Photothermal Effect for Cancer Theranostics.

Combination therapy based on different mechanisms of cell death has shown promise in tumor therapy. However, when different modalities are integrated, the maximum synergy of the therapeutic effects is often lacking in the design. Herein, we report a cancer theranostic nanomedicine formula developed by considering the mechanisms of action of ferroptosis and the photothermal effect in combination therapy. The croconaine molecule was encapsulated as both a photothermal converter and an iron-chelating agent with BSA, thus leading to biocompatible and stable Cro-Fe@BSA nanoparticles (NPs). The Cro-Fe@BSA NPs in the tumor milieu showed an activated photothermal effect leading to enhanced radical formation owing to the temperature-dependent Fenton reaction kinetics, while radical formation during ferroptosis in turn prevented the heat-induced formation of heat shock proteins and thus the self-protection mechanism of cancer cells in response to heat. The activatable photoacoustic and magnetic resonance imaging performance of the Cro-Fe@BSA NPs also enabled safe and reliable cancer theranostics.

A Novel Cascade Nanoreactor Integrating Two-Dimensional Pd-Ru Nanozyme, Uricase and Red Blood Cell Membrane for Highly Efficient Hyperuricemia Treatment.

Nanozyme-based cascade reaction has emerged as an effective strategy for disease treatment because of its high efficiency and low side effects. Herein, a new and highly active two-dimensional Pd-Ru nanozyme is prepared and then integrated with uricase and red blood cell (RBC) membrane to fabricate a tandem nanoreactor, Pd-Ru/Uricase@RBC, for hyperuricemia treatment. The designed Pd-Ru/Uricase@RBC nanoreactor displayed not only good stability against extreme pH, temperature and proteolytic degradation, but also long circulation half-life and excellent safety. The nanoreactor can effectively degrade UA by uricase to allantoin and H2 O2 and remove H2 O2 by using Pd-Ru nanosheets (NSs) with the catalase (CAT)-like activity. More importantly, the finally produced O2 from H2 O2 decomposition can in turn facilitate the catalytic oxidation of UA, as the degradation of UA is an O2 consumption process. By integrating the high-efficiency enzymatic activity, long circulation capability, and good biocompatibility, the designed Pd-Ru/Uricase@RBC can effectively and safely treat hyperuricemia without side effects. The study affords a new alternative for the exploration of clinical treatment of hyperuricemia.

Radioiodinated Portable Albumin Binder as a Versatile Agent for in Vivo Imaging with Single-Photon Emission Computed Tomography.

In this study, radioiodinated 4-( p-iodophenyl)butyric acid ([131I]IBA) was synthesized and evaluated as a portable albumin-binder for potential applications in single photon emission computed tomography imaging of blood pool, tumor, and lymph node with significantly improved pharmacokinetic properties. The [131I]IBA was prepared under the catalyst of Cu2O/1,10-phenanthroline. After that, the albumin-binding capability of [131I]IBA was tested in vitro, ex vivo, and in vivo, respectively. [131I]IBA was obtained with very high radiolabeling yield (>99%) and good radiochemical purity (>98%) within 10 min. It binds to albumin effectively with high affinity (IC50= 46.5 µM) and has good stability. The results of biodistribution indicated that the [131I]IBA was mainly accumulated in blood with good retention (10.51 ± 2.58%ID/g at 30 min p.i. and 4.63 ± 0.17%ID/g at 4 h p.i.). In the SPECT imaging of mice models with [131I]IBA, blood pool, lymph node, and tumors could be imaged clearly with high target-to-background ratio. Overall, the radioiodinated albumin binder of [131I]IBA with long blood half-life and excellent stability could be used to decorate diversified albumin-binding radioligands and developed as a versatile theranostic agent.

Reprogramming Tumor-Associated Macrophages by Nanoparticle-Based Reactive Oxygen Species Photogeneration.

Without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment, cancer immunotherapy generally offers limited clinical benefit for established tumors. Tumor-associated macrophages (TAMs) are the critical driver of this immunosuppressive tumor microenvironment, which also promotes tumor metastasis. Here we successfully reprogrammed TAMs to an antitumor M1 phenotype using precision nanoparticle-based reactive oxygen species photogeneration, which demonstrated superior efficiency and efficacy over lipopolysaccharide stimulation. Meanwhile, antigen presentation and T-cell-priming by TAMs were enhanced by inhibiting lysosomal proton pump and proteolytic activity or by promoting tumor associated antigen release in the cytoplasm. The reprogrammed TAMs orchestrate cytotoxic lymphocyte (CTL) recruitment in the tumor and direct memory T-cells toward tumoricidal responses. This strategy could effectively eradicate tumors, inhibit metastasis, and further prevent their recurrence, which holds tremendous promise to realize potent cancer immunotherapy.

Highly Specific and Sensitive Radioiodinated Agent for In Vivo Imaging of Superoxide through Superoxide-Initiated Retention.

Superoxide (O2•-) is a specific molecular target for xenobiotics, cytokines, and bacteria during inflammatory diseases. The aim of this study is to develop a single-photon emission computed tomography (SPECT) imaging agent and to quantify the distribution of O2•- in vivo. 125/131I-PISO was obtained in good radiochemical yield (65.4 ± 9.2%) and high radiochemical purity (>98%) after HPLC purification. 125/131I-PISO (log P = 2.46) could be oxidized by O2•- selectively and sensitively, converted to a hydrophilic compound 125/131I-PISA (log P = -1.62) with negative charge simultaneously and conglutinated with biomolecules by electrostatic interactions. The specific accumulation of 131I-PISA in the O2•- rich region were verified in cell efflux assay and SPECT/CT imaging in situ O2•- enrichment model mice. SPECT/CT imaging showed higher accumulation of 125I-PISO in the inflamed ankles compared to the control. Radioiodinated PISO is a potential SPECT agent to image O2•- distribution in vivo through specific and sensitive O2•- triggered retention.

Radioiodinated Pentixather for SPECT Imaging of Expression of the Chemokine Receptor CXCR4 in Rat Myocardial-Infarction-Reperfusion Models.

The purpose of this study is to develop a specific CXCR4-targeting radioiodinated agent (125I- or 131I-pentixather) for single-photon-emission-computed-tomography (SPECT) imaging of CXCR4 expression in myocardial-infarction-reperfusion (MI/R) rat models. After SPECT-CT imaging with 125I-pentixather at 4, 12, and 36 h and 3 and 7 days after MI/R, the models were validated by ex vivo autoradiography, TTC staining, and immunohistochemistry and in vivo echocardiography and classical 99mTc-MIBI perfusion imaging. The SPECT-CT images showed that the infarcted myocardium (IM) could be visualized with high quality as early as 4 h and reached the maximum at 3 days after MI/R and that CXCR4 upregulation was still visible at 7 days after MI/R. In the biodistribution study, high uptakes in the IM (0.99 ± 0.13, 1.52 ± 0.29, 1.75 ± 0.22, 1.94 ± 0.27, and 0.61 ± 0.14% ID/g at 4, 12, and 36 h and 3 and 7 days after MI/R, respectively) were observed that were much higher than that of normal myocardium. The highest uptake was reached at 3 days after MI/R, which agreed well with the SPECT results. In addition, the radioactivity uptakes of the IM in both the biodistribution and SPECT imaging could be blocked effectively by excess amounts of AMD3465, indicating the high specificity of radioiodinated pentixather to CXCR4. On the basis of its promising properties, 125I-pentixather may serve as a powerful CXCR4-expression diagnostic probe for evaluating lesions and monitoring therapy responses in patients with cardiovascular diseases.

Development of a New FR-Targeting Agent 99mTc-HYNFA with Improved Imaging Contrast and Comparison of Multimerization and/or PEGylation Strategies for Radio-Folate Modification.

This study aims to develop a new folate receptor (FR)-targeting agent for SPECT imaging with improved contrast and evaluate the modification strategies of multimerization and/or PEGylation in the development of new radio-folates. A series of novel folate derivatives have been synthesized and radiolabeled with 99mTc using tricine and TPPTS as coligands. To better investigate their pharmacokinetics, cell uptake, biodistribution, and microSPECT/CT imaging were evaluated. Four radioligands displayed high KB cell uptake after incubation for 2 and 4 h. Presaturated with excess folic acid (FA) resulted in a significant blocking effect in KB cells, indicating specificity of these radioligands toward FR. Biodistribution and microSPECT imaging studies in KB tumor-bearing mice showed that the folate conjugate 99mTc-HYNFA with poly(ethylene glycol) (PEG) and triazole linkage displayed the highest tumor uptake (16.30 ± 2.01 %ID/g at 2 h p.i. and 14.9 ± 0.62 %ID/g at 4 h p.i. in mice biodistribution) and best imaging contrast, indicating promising application prospect. More interestingly, the in vivo performance of this monomeric 99mTc-HYNFA was much better than that of FA multimers and non-PEGylated monomers, suggesting that multimerization may not be a feasible method for the design of radio-folates. PEG linkage rather than FA multimerization should be taken into consideration in the development of folate-based radiopharmaceuticals in the future.

Cinnamic Acid (CINN) Induces Apoptosis and Proliferation in Human Nasopharyngeal Carcinoma Cells.

BACKGROUND/AIMS: CINN is the main ingredient of the traditional Chinese medicine cinnamon. The purpose of the present study was to investigate the effects of CINN on the proliferation and apoptosis of NPC cells and to elucidate the underlying molecular mechanisms. MATERIALS AND METHODS: CNE2 human NPC cells were treated with various CINN concentrations. The effects of CINN on the proliferation and apoptosis of CNE2 NPC cells were examined using the MTT assay and flow cytometric analysis. Additionally, western blotting was performed to analyze the expression of a number of cell cycle- and apoptosis-related proteins. RESULTS: The proliferation of CNE2 cells was significantly inhibited after treatment with different CINN concentrations for various lengths of time. The inhibitory effect of CINN was concentration-and time-dependent. Flow cytometric analysis showed that 2 mmol/L CINN displayed a significant apoptosis-inducing effect. The western blot analysis results showed that KLF6, Fas-L, Bax, P53 and caspase-3 protein expression was drastically increased in the CNE2 cells after treatment with 2 mmol/L CINN, whereas Bcl-2 and cyclin D1 protein expression was markedly reduced. CONCLUSION: CINN inhibits the proliferation and induces the apoptosis of CNE2 cells. Therefore, CINN possesses a potential anti-tumor effect.

Synthesis and Evaluation of (99m)Tc-Labeled Dimeric Folic Acid for FR-Targeting.

The folate receptor (FR) is overexpressed in a wide variety of human tumors. In our study, the multimeric concept was used to synthesize a dimeric folate derivative via a click reaction. The novel folate derivative (HYNIC-D1-FA2) was radiolabeled with (99m)Tc using tricine and trisodium triphenylphosphine-3,3',3″-trisulfonate (TPPTS) as coligands ((99m)Tc-HYNIC-D1-FA2) and its in vitro physicochemical properties, ex vivo biodistribution and in vivo micro-SPECT/CT imaging as a potential FR targeted agent were evaluated. It is a hydrophilic compound (log P = -2.52 ± 0.13) with high binding affinity (IC50 = 19.06 nM). Biodistribution in KB tumor-bearing mice showed that (99m)Tc-HYNIC-D1-FA2 had high uptake in FR overexpressed tumor and kidney at all time-points, and both of them could obviously be inhibited when blocking with free FA in the blocking studies. From the in vivo micro-SPECT/CT imaging results, good tumor uptake of (99m)Tc-HYNIC-D1-FA2 was observed in KB tumor-bearing mice and it could be blocked obviously. Based on the results, this new radiolabeled dimeric FA tracer might be a promising candidate for FR-targeting imaging with high affinity and selectivity.

A segmentation network for farmland ridge based on encoder-decoder architecture in combined with strip pooling module and ASPP.

In order to effectively support wheat breeding, farmland ridge segmentation can be used to visualize the size and spacing of a wheat field. At the same time, accurate ridge information collecting can deliver useful data support for farmland management. However, in the farming ridge segmentation scenarios based on remote sensing photos, the commonly used semantic segmentation methods tend to overlook the ridge edges and ridge strip features, which impair the segmentation effect. In order to efficiently collect ridge information, this paper proposes a segmentation method based on encoder-decoder of network with strip pooling module and ASPP module. First, in order to extract context information for multi-scale features, ASPP module are integrated in the deepest feature map. Second, the remote dependence of the ridge features is improved in both horizontal and vertical directions by using the strip pooling module. The final segmentation map is generated by fusing the boundary features and semantic features using an encoder and decoder architecture. As a result, the accuracy of the proposed method in the validation set is 98.0% and mIoU is 94.6%. The results of the experiments demonstrate that the method suggested in this paper can precisely segment the ridge information, as well as its value in obtaining data on the distribution of farmland and its potential for practical application.

Coassembly Nanomedicine Mediated by Intermolecular Interactions Between Methotrexate and Baricitinib for Improved Rheumatoid Arthritis Treatment.

The combination of anti-rheumatoid arthritis (RA) drugs methotrexate (MTX) and baricitinib (BTN) has been reported to improve RA treatment efficacy. However, study on the strategy of combination is elusive when considering the benefit of the synergy between MTX and BTN. In this study, we found that the N-heterocyclic rings in the MTX and BTN offer hydrogen bonds and π-π stacking interactions, driving the formation of exquisite vesicular morphology of nanovesicles, denoted as MB NVs. The MB NVs with the MTX/BTN weight ratio of 2:1, MB NVs (2:1), showed an improved anti-RA effect through the synergy between the anti-inflammatory and antiproliferative responses. This work presents that the intermolecular interactions between drug molecules could mediate the coassembly behavior into nanomedicine as well as the therapy synergy both in vitro and in vivo, which may provide further understanding on the rational design of combination nanomedicine for therapeutic purposes.

A Dual-domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration.

Chronic hepatitis B (CHB) remains a major public health concern because of the inefficiency of currently approved therapies in clearing the hepatitis B surface antigen (HBsAg). Antibody-based regimens have demonstrated potency regarding virus neutralization and HBsAg clearance. However, high dosages or frequent dosing are required for virologic control. In this study, a dual-domain-engineered anti-hepatitis B virus (HBV) therapeutic antibody 73-DY is developed that exhibits significantly improved efficacy regarding both serum and intrahepatic viral clearance. In HBV-tolerant mice, administration of a single dose of 73-DY at 2 mg kg-1 is sufficient to reduce serum HBsAg by over 3 log10 IU mL-1 and suppress HBsAg to < 100 IU mL-1 for two weeks, demonstrating a dose-lowering advantage of at least tenfold. Furthermore, 10 mg kg-1 of 73-DY sustainably suppressed serum viral levels to undetectable levels for ≈ 2 weeks. Molecular analyses indicate that the improved efficacy exhibited by 73-DY is attributable to the synergy between fragment antigen binding (Fab) and fragment crystallizable (Fc) engineering, which conferred sustained viral suppression and robust viral eradication, respectively. Long-term immunotherapy with reverse chimeric 73-DY facilitated the restoration of anti-HBV immune responses. This study provides a foundation for the development of next-generation antibody-based CHB therapies.

Membrane Proteins and Membrane Curvature: Mutual Interactions and a Perspective on Disease Treatments.

The pathogenesis of various diseases often involves an intricate interplay between membrane proteins and membrane curvature. Understanding the underlying mechanisms of this interaction could offer novel perspectives on disease treatment. In this review, we provide an introduction to membrane curvature and its association with membrane proteins. Furthermore, we delve into the impact and potential implications of this interaction in the context of disease treatment. Lastly, we discuss the prospects and challenges associated with harnessing these interactions for effective disease management, aiming to provide fresh insights into therapeutic strategies.

Selective depolymerization of sugarcane bagasse anaerobic digestate to highly stable phenols-rich bio-oil with the iron-doped K-feldspar catalyst.

Sustainable implementation of thermochemical conversion of biomass to targeted products is dependent on innovations in catalyst design and tuning of structure-property relationships. This study details the use of potassium feldspar (K-feldspar) as a support doped with different iron (Fe) concentrations via wet impregnation (WI) method for hydrothermal liquefaction (HTL) of sugarcane bagasse anaerobic digestate. The Fe/K-feldspar supported catalysts were synthesized and characterized using X-ray diffraction, Inductively Coupled Plasma Optical Emission spectroscopy, Brunauer-Emmet-Teller and Scanning Electron Microscopy analytical methods. Amongst all the catalysts, K-feldspar dopped with 10 wt% Fe (WI-10) was more effective, producing 51.2 wt% bio-crude. The catalyst's activity has been related to the balanced proportion of the microcline: sanidine: haematite (2.8:3.3:1) phases of Fe present on the catalyst, the surface area (porosity), and the surface functionality, thus conferring desirable activity properties. In addition, the WI-10 catalyst had a better selectivity towards substituted phenols that can potentially be used for higher-value applications such as the production of Nylons 6 and 66, and bioplastics. The bio-oil produced with WI-10 has also been demonstrated to be highly stable. The catalyst was reusable up to four times maintaining moderate catalytic performance, and a simple regeneration protocol was shown to restore the activity of the catalyst. The resulting solid residue also exhibited promise as a viable material for use in electrodes for Lithium-ion batteries (LiB). Therefore, this research has demonstrated a promising and sustainable resource recovery strategy for valorising wet biomass wastes into streams of useful products for valuable chemical production and energy application.

Magnetic Resonance Imaging Nanoprobe Quantifies Nitric Oxide for Evaluating M1/M2 Macrophage Polarization and Prognosis of Cancer Treatments.

Macrophages play a crucial role in immune activation and provide great value in the prognosis of cancer treatments. Current strategies for prognostic evaluation of macrophages mainly target the specific biomarkers to reveal the number and distribution of macrophages in the tumors, whereas the phenotypic change of M1 and M2 macrophages in situ is less understood. Here, we designed an ultrasmall superparamagnetic iron oxide nanoparticle-based molecular imaging nanoprobe to quantify the repolarization of M2 to M1 macrophages by magnetic resonance imaging (MRI) using the redox-active nitric oxide (NO) as a vivid chemical target. The nanoprobe equipped with O-phenylenediamine groups could react with the intracellular NO molecules during the repolarization of M2 macrophages to the M1 phenotype, leading to electrical attraction and colloidal aggregation of the nanoprobes. Consequently, the prominent changes of the T1 and T2 relaxation in MRI allow for the quantification of the macrophage polarization. In a 4T1 breast cancer model, the MRI nanoprobe was able to reveal macrophage polarization and predict treatment efficiency in both immunotherapy and radiotherapy paradigms. This study presents a noninvasive approach to monitor the phenotypic changes of M2 to M1 macrophages in the tumors, providing insight into the prognostic evaluation of cancer treatments regarding macrophage-mediated immune responses.

Ferroptosis MRI for early detection of anticancer drug-induced acute cardiac/kidney injuries.

Ferroptosis has been realized in anticancer drug-induced acute cardiac/kidney injuries (ACI/AKI); however, molecular imaging approach to detect ferroptosis in ACI/AKI is a challenge. We report an artemisinin-based probe (Art-Gd) for contrast-enhanced magnetic resonance imaging of ferroptosis (feMRI) by exploiting the redox-active Fe(II) as a vivid chemical target. In vivo, the Art-Gd probe showed great feasibility in early diagnosis of anticancer drug-induced ACI/AKI, which was at least 24 and 48 hours earlier than the standard clinical assays for assessing ACI and AKI, respectively. Furthermore, the feMRI was able to provide imaging evidence for the different mechanisms of action of ferroptosis-targeted agents, either by blocking lipid peroxidation or depleting iron ions. This study presents a feMRI strategy with simple chemistry and robust efficacy for early evaluation of anticancer drug-induced ACI/AKI, which may shed light on the theranostics of a variety of ferroptosis-related diseases.