An Oxidative Stress Nano-Amplifier for Improved Tumor Elimination and Combined Immunotherapy.

Amplifying oxidative stress to disrupt intracellular redox homeostasis can accelerate tumor cell death. In this work, an oxidative stress amplifier (PP@T) is prepared for enhanced tumor oxidation therapy to reduce tumor growth and metastases. The nano-amplifier has been successfully constructed by embedding MTH1 inhibitor (TH588) in the PDA-coated porphyrin metal-organic framework PCN-224. The controllable-released TH588 is demonstrated from pores can hinder MTH1-mediated damage-repairing process by preventing the hydrolysis of 8-oxo-dG, thereby amplifying oxidative stress and exacerbating the oxidative DNA damage induced by the sonodynamic therapy of PP@T under ultrasound irradiation. Furthermore, PP@T can effectively induce immunogenic cell death to trigger systemic anti-tumor immune response. When administered in combination with immune checkpoint blockade, PP@T not only impedes the progression of the primary tumor but also achieves obvious antimetastasis in breast cancer murine models, including orthotopic and artificial whole-body metastasis models. Furthermore, the nanoplatform also provides photoacoustic imaging for in vivo treatment guidance. In conclusion, by amplifying oxidative stress and reactive oxygen species sensitized immunotherapy, this image-guided nanosystem shows potential for highly specific, effective combined therapy against tumor cells with negligible side-effects to normal cells which will provide a new insight for precise tumor treatment.

Metal-ion-chelating phenylalanine nanostructures reverse immune dysfunction and sensitize breast tumour to immune checkpoint blockade.

An immunosuppressive tumour microenvironment strongly influences response rates in patients receiving immune checkpoint blockade-based cancer immunotherapies, such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1). Here we demonstrate that metal-ion-chelating L-phenylalanine nanostructures synergize with short-term starvation (STS) to remodel the immunosuppressive microenvironment of breast and colorectal tumours. These nanostructures modulate the electrophysiological behaviour of dendritic cells and activate them through the NLRP3 inflammasome and calcium-mediated nuclear factor-κB pathway. STS promotes the cellular uptake of nanostructures through amino acid transporters and plays a key role in dendritic cell maturation and tumour-specific cytotoxic T lymphocyte responses. This study demonstrates the potential role of metal-ion-chelating L-phenylalanine nanostructures in activating immune responses and the effect of STS treatment in improving nanomaterial-mediated cancer immunotherapy.

Breakthrough of Hypoxia Limitation by Tumor-Targeting Photothermal Therapy-Enhanced Radiation Therapy.

Purpose: To address the problem of suboptimal reactive oxygen species (ROS) production in Radiation therapy (RT) which was resulted from exacerbated tumor hypoxia and the heterogeneous distribution of radiation sensitizers. Materials and Methods: In this work, a novel nanomedicine, designated as PLGA@IR780-Bi-DTPA (PIBD), was engineered by loading the radiation sensitizer Bi-DTPA and the photothermal agent IR780 onto poly(lactic-co-glycolic acid) (PLGA). This design leverages the tumor-targeting ability of IR780 to ensure selective accumulation of the nanoparticles in tumor cells, particularly within the mitochondria. The effect of the photothermal therapy-enhanced radiation therapy was also examined to assess the alleviation of hypoxia and the enhancement of radiation sensitivity. Results: The PIBD nanoparticles exhibited strong capacity in mitochondrial targeting and selective tumor accumulation. Upon activation by 808 nm laser irradiation, the nanoparticles effectively alleviated local hypoxia by photothermal effect enhanced blood supplying to improve oxygen content, thereby enhancing the ROS production for effective RT. Comparative studies revealed that PIBD-induced RT significantly outperformed conventional RT in treating hypoxic tumors. Conclusion: This design of tumor-targeting photothermal therapy-enhanced radiation therapy nanomedicine would advance the development of targeted drug delivery system for effective RT regardless of hypoxic microenvironment.

Potentiating dual-directional immunometabolic regulation with nanomedicine to enhance anti-tumor immunotherapy following incomplete photothermal ablation.

Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However, incomplete PTT can leave residual tumors that often lead to new metastases and decreased patient survival in clinical scenarios. This is primarily due to the release of ATP, a damage-associated molecular pattern that quickly transforms into the immunosuppressive metabolite adenosine by CD39, prevalent in the tumor microenvironment, thus promoting tumor immune evasion. This study presents a photothermal nanomedicine fabricated by electrostatic adsorption among the Fe-doped polydiaminopyridine (Fe-PDAP), indocyanine green (ICG), and CD39 inhibitor sodium polyoxotungstate (POM-1). The constructed Fe-PDAP@ICG@POM-1 (FIP) can induce tumor PTT and immunogenic cell death when exposed to a near-infrared laser. Significantly, it can inhibit the ATP-adenosine pathway by dual-directional immunometabolic regulation, resulting in increased ATP levels and decreased adenosine synthesis, which ultimately reverses the immunosuppressive microenvironment and increases the susceptibility of immune checkpoint blockade (aPD-1) therapy. With the aid of aPD-1, the dual-directional immunometabolic regulation strategy mediated by FIP can effectively suppress/eradicate primary and distant tumors and evoke long-term solid immunological memory. This study presents an immunometabolic control strategy to offer a salvage option for treating residual tumors following incomplete PTT.

Metallic Copper-Based Dual-Enzyme Biomimetic Nanoplatform for Mild Photothermal Enhancement of Anticancer Catalytic Activity.

Background: Chemodynamic therapy (CDT) is recognized as a promising cancer treatment. Recently, copper sulfide nanostructures have been extensively employed as Fenton-like reagents that catalyze the formation of acutely toxic hydroxyl radicals (·OH) from hydrogen peroxide (H2O2). However, CDT therapeutic potency is restricted by the tumor microenvironment (TME), such as insufficient amounts of hydrogen peroxide, excessive glutathione levels, etc. To address these disadvantages, glucose oxidase (GOx) or catalase (CAT) can be utilized to enhance CDT, while low therapeutic efficacy still inhibits their future applications. Our previous study revealed that mild photothermal effect could boost the CDT catalytic effectiveness as well as GOx enzyme activity over a range. Results: We engineered and constructed a hollow CuS nanoplatform loaded with GOx and CAT, coating with macrophage membranes (M@GOx-CAT@CuS NPs). The nanoplatforms allowed enhancement of the reactive oxygen species creation rate and GOx catalytic activeness of CDT through mild phototherapy directed by photoacoustic imaging. After actively targeting vascular cell adhesion molecule-1 (VCAM-1) in cancer cells mediated by macrophage membrane coating, M@GOx-CAT@CuS NPs released GOx and CAT under near-infrared irradiation. GOx catalyzed the formation of H2O2 and gluconic acid with glucose, creating a better catalytic environment for CDT. Meanwhile, CAT-catalyzed H2O2 decomposition to generate sufficient oxygen, appropriately alleviating the oxygen shortage in the TME. In addition, starvation effects decreased adenosine triphosphate levels and further underregulated heat shock protein expression to reduce the heat resistance of tumor cells, resulting in a better mild phototherapy outcome. Both in vitro and in vivo experiments demonstrated that the newly developed M@GOx-CAT@CuS nanoplatform has remarkable synergistic anticancer therapeutic effects. Conclusion: The cascade reaction-enhanced biomimetic nanoplatform opens up a new avenue for precision tumor diagnostic and therapeutic research.

Amplifying STING Activation and Alleviating Immunosuppression through a Mn2+-Based Metal-Organic Framework Nanosystem for Synergistic Cancer Therapy.

The field of immunotherapy, particularly immune checkpoint blockade (ICB), holds immense potential in mitigating the progression of cancer. However, the challenges of insufficient tumor antigen production and the immunosuppressive state in the tumor microenvironment substantially impede patients from deriving benefits. In this research, we present a tumor-microenvironment-modulation manganese-based nanosystem, PEG-MnMOF@PTX, aiming to improve the responsiveness of ICB. Under acidic conditions, the released Mn2+ accomplishes multiple objectives. It generates toxic hydroxyl radicals (•OH), together with the released paclitaxel (PTX), inducing immunogenic cell death of tumor cells and normalizing tumor blood vessels. Concurrently, it facilitates the in situ generation of oxygen (O2) from hydrogen peroxide (H2O2), ameliorating the microenvironmental immunosuppression and increasing the efficacy of immunotherapy. In addition, this study demonstrates that PEG-MnMOF@PTX can promote the maturation of dendritic cells and augment the infiltration of cytotoxic T lymphocytes through activation of the cyclic guanosine 5'-monophosphate-adenosine 5'-monophosphate synthase (cGAS) and interferon gene stimulator (STING) pathways, namely cGAS-STING pathways, thereby heightening the sensitivity to ICB immunotherapy. The findings of this study present a novel paradigm for the progress in cancer immunotherapy.

Combination of MHI148 Targeted Photodynamic Therapy and STING Activation Inhibits Tumor Metastasis and Recurrence.

Metastasis and recurrence are notable contributors to mortality associated with breast cancer. Although immunotherapy has shown promise in mitigating these risks after conventional treatments, its effectiveness remains constrained by significant challenges, such as impaired antigen presentation by dendritic cells (DCs) and inadequate T cell infiltration into tumor tissues. To address these limitations, we developed a multifunctional nanoparticle platform, termed GM@P, which consisted of a hydrophobic shell encapsulating the photosensitizer MHI148 and a hydrophilic core containing the STING agonist 2'3'-cGAMP. This design elicited robust type I interferon responses to activate antitumor immunity. The GM@P nanoparticles loaded with MHI148 specifically targeted breast cancer cells. Upon exposure to 808 nm laser irradiation, the MHI148-loaded nanoparticles produced toxic reactive oxygen species (ROS) to eradicate tumor cells through photodynamic therapy (PDT). Notably, PDT stimulated immunogenic cell death (ICD) to foster the potency of antitumor immune responses. Furthermore, the superior photoacoustic imaging (PAI) capabilities of MHI148 enabled the simultaneous visualization of diagnostic and therapeutic procedures. Collectively, our findings uncovered that the combination of PDT and STING activation facilitated a more conducive immune microenvironment, characterized by enhanced DC maturation, infiltration of CD8+ T cells, and proinflammatory cytokine release. This strategy stimulated local immune responses to augment systemic antitumor effects, offering a promising approach to suppress tumor growth, inhibit metastasis, and prevent recurrence.

NIR-responsive copper nanoliposome composites for cascaded ferrotherapy via ferroptosis actived ICD and IFN-γ released.

Metallic biomaterials activate tumor ferroptosis by increasing oxidative stress, but their efficacy is severely limited in tumor microenvironment. Although interferon gamma (IFN-γ) can promote tumor ferroptosis sensitivity by inhibiting the antioxidant system and promoting lipid accumulation, this effect limited by the lack of IFN-γ accumulation in tumors. Herein, we report a near-infrared (NIR)-responsive HCuS nanocomposite (HCuS-PE@TSL-tlyp-1) that can stimulate immunogenic cell death (ICD)-mediated IFN-γ secretion through exogenous oxidative stress, thereby achieving cascaded ferrotherapy by mutually reinforcing ferroptosis and systemic immunity. Upon laser irradiation, the dissolution of the thermal coating, and the introduction of Cu ions and piperazine-erastin (PE) simultaneously induce oxidative stress by reactive oxygen species (ROS)/lipid peroxide (LPO) accumulation and deplete cystine-glutamate transporter (xCT)/GSH. The onset of oxidative stress-mediated ferroptosis is thus achieved, and ICD is triggered, significantly promoting cytotoxic T-cell (CTL) infiltration for IFN-γ secretion. Furthermore, IFN-γ induces immunogenic tumor ferroptosis by inhibiting xCT-antioxidant pathways and enhancing the ACSL4-fatty acid recruitment pathway, which further promotes sensitivity to ferroptosis in cells. These HCuS nanocomposites combined with aPD-L1 effectively in inhibiting tumor metastasis and recurrence. Importantly, these cascade ferrotherapy results broadens the application of HCuS biomaterials.

Proton Sponge Nanocomposites for Synergistic Tumor Elimination via Autophagy Inhibition-Promoted Cell Apoptosis and Macrophage Repolarization-Enhanced Immune Response.

Cytoprotective autophagy and an immunosuppressive tumor microenvironment (TME) are two positive promoters for tumor proliferation and metastasis that severely hinder therapeutic efficacy. Inhibiting autophagy and reconstructing TME toward macrophage activation simultaneously are of great promise for effective tumor elimination, yet are still a huge challenge. Herein, a kind of dendrimer-based proton sponge nanocomposites was designed and constructed for tumor chemo/chemodynamic/immunotherapy through autophagy inhibition-promoted cell apoptosis and macrophage repolarization-enhanced immune response. These obtained nanocomposites contain a proton sponge G5AcP dendrimer, a Fenton-like agent Cu(II), and chemical drug doxorubicin (DOX). When accumulated in tumor regions, G5AcP can act as an immunomodulator to realize deacidification-promoted macrophage repolarization toward antitumoral type, which then secretes inflammatory cytokines to activate T cells. They also regulate intracellular lysosomal pH to inhibit cytoprotective autophagy. The released Cu(II) and DOX can induce aggravated damage through a Fenton-like reaction and chemotherapeutic effect in this autophagy-inhibition condition. Tumor-associated antigens are released from these dying tumor cells to promote the maturity of dendritic cells, further activating T cells. Effective tumor elimination can be achieved by this dendrimer-based therapeutic strategy, providing significant guidance for the design of a promising antitumor nanomedicine.

Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy.

BACKGROUND: Breast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA. RESULTS: Nanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC. CONCLUSION: The two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC.

Smart responsive Fe/Mn nanovaccine triggers liver cancer immunotherapy via pyroptosis and pyroptosis-boosted cGAS-STING activation.

BACKGROUND: The prognosis for hepatocellular carcinoma (HCC) remains suboptimal, characterized by high recurrence and metastasis rates. Although metalloimmunotherapy has shown potential in combating tumor proliferation, recurrence and metastasis, current apoptosis-based metalloimmunotherapy fails to elicit sufficient immune response for HCC. RESULTS: A smart responsive bimetallic nanovaccine was constructed to induce immunogenic cell death (ICD) through pyroptosis and enhance the efficacy of the cGAS-STING pathway. The nanovaccine was composed of manganese-doped mesoporous silica as a carrier, loaded with sorafenib (SOR) and modified with MIL-100 (Fe), where Fe3+, SOR, and Mn2+ were synchronized and released into the tumor with the help of the tumor microenvironment (TME). Afterward, Fe3+ worked synergistically with SOR-induced immunogenic pyroptosis (via both the classical and nonclassical signaling pathways), causing the outflow of abundant immunogenic factors, which contributes to dendritic cell (DC) maturation, and the exposure of double-stranded DNA (dsDNA). Subsequently, the exposed dsDNA and Mn2+ jointly activated the cGAS-STING pathway and induced the release of type I interferons, which further led to DC maturation. Moreover, Mn2+-related T1 magnetic resonance imaging (MRI) was used to visually evaluate the smart response functionality of the nanovaccine. CONCLUSION: The utilization of metallic nanovaccines to induce pyroptosis-mediated immune activation provides a promising paradigm for HCC treatment.

Self-Reinforced Bimetallic Mito-Jammer for Ca2+ Overload-Mediated Cascade Mitochondrial Damage for Cancer Cuproptosis Sensitization.

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

Collagen-Targeting Self-Assembled Nanoprobes for Multimodal Molecular Imaging and Quantification of Myocardial Fibrosis in a Rat Model of Myocardial Infarction.

Currently, inadequate early diagnostic methods hinder the prompt treatment of patients with heart failure and myocardial fibrosis. Magnetic resonance imaging is the gold standard noninvasive diagnostic method; however, its effectiveness is constrained by low resolution and challenges posed by certain patients who cannot undergo the procedure. Although enhanced computed tomography (CT) offers high resolution, challenges arise owing to the unclear differentiation between fibrotic and normal myocardial tissue. Furthermore, although echocardiography is real-time and convenient, it lacks the necessary resolution for detecting fibrotic myocardium, thus limiting its value in fibrosis detection. Inspired by the postinfarction accumulation of collagen types I and III, we developed a collagen-targeted multimodal imaging nanoplatform, CNA35-GP@NPs, comprising lipid nanoparticles (NPs), encapsulating gold nanorods (GNRs) and perfluoropentane (PFP). This platform facilitated ultrasound/photoacoustic/CT imaging of postinfarction cardiac fibrosis in a rat model of myocardial infarction (MI). The surface-modified peptide CNA35 exhibited excellent collagen fiber targeting. The strong near-infrared light absorption and substantial X-ray attenuation of the nanoplatform rendered it suitable for photoacoustic and CT imaging. In the rat model of MI, our study demonstrated that CNA35-GNR/PFP@NPs (CNA35-GP@NPs) achieved photoacoustic, ultrasound, and enhanced CT imaging of the fibrotic myocardium. Notably, the photoacoustic signal intensity positively correlated with the severity of myocardial fibrosis. Thus, this study presents a promising approach for accurately detecting and treating the fibrotic myocardium.

Advances in imaging of the lacrimal gland in Sjögren's syndrome: A narrative review.

Due to lymphocytic infiltration of the salivary and lacrimal glands, Sjogren's syndrome (SS), a systemic autoimmune illness that mostly affects the exocrine glands, causes dry mouth (xerostomia) and dry eyes (xerophthalmia). Additionally, SS is associated with various comorbidities such as cardiovascular diseases, infections, musculoskeletal diseases, and cancers. Among patients with SS, xerophthalmia frequently arises as a complication, leading to insufficient tear production or rapid tear evaporation, thereby causing discomfort, irritation, and a gritty sensation in the eyes. This article aims to examine recent advancements in the imaging of the lacrimal gland in Sjögren's syndrome and briefly discusses the utilization of various imaging examinations for the lacrimal gland in this particular disease.

Two-dimensional speckle tracking imaging analyses of the correlations between left atrial appendage function and stroke risk in nonvalvular atrial fibrillation patients.

Stroke incidence is the most severe complication associated with atrial fibrillation (AF), and the most common site of thrombus formation in AF patients is the left atrial appendage (LAA). This study was developed to use two-dimensional speckle tracking imaging (2D-STI) to explore associations between LAA strain/strain rate and stroke incidence and to evaluate the value of utilizing LAA strain and strain rate values to support the stratification of nonvalvular AF (NVAF) patients based on stroke risk. A total of 486 AF patients who had undergone transesophageal echocardiography to exclude potential intracardiac thrombosis between March 2021 and November 2022 were consecutively enrolled. Patients meeting the inclusion criteria were separated into two groups according to their history of stroke/transient ischemic attack (TIA). LAA strain and strain rate values in these patients were measured via 2D-STI. Multivariable logistic regression analysis was employed to determine independent risk factors for the construction of a combined predictive model. Of the 333 analyzed patients (134 females, aged 65 (56,72) years), 39 (11.71%, 39/333) had a history of stroke at the time of evaluation. Multivariate logistic regression analysis demonstrated that nonparoxysmal AF, CHA2DS2VASc score, LAA thrombus/spontaneous echo contrast (SEC), LAA strain, and strain rate were all predictors of stroke incidence among NVAF patients. The combined predictive model demonstrated excellent discriminative ability, with an AUC of 0.91 (95%CI 0.87-0.95, P < 0.001), and a sensitivity and specificity of 79.49% and 89.46%, respectively. The Hosmer-Lemeshow test confirmed good calibration, yielding a value of 0.98. Comparative decision curve analysis showed that the model provided superior net benefits compared to the CHA2DS2VASc score. Furthermore, the model exhibited improved predictive performance and reclassification for stroke when compared to the CHA2DS2VASc score (AUC 0.91 vs. 0.88, Z = 2.32, P = 0.02), accompanied by a significant increase in the net reclassification index (+ 5.44%, P < 0.001) and integrated discrimination improvement (8.21%, P < 0.001). These data demonstrate that LAA strain and strain rate, as measured via 2D-STI, can offer value when assessing LAA function in AF patients, potentially providing further predictive value to extant clinical risk scoring strategies.

Expression of Concern: Low-intensity focused ultrasound (LIFU)-activated nanodroplets as a theranostic agent for noninvasive cancer molecular imaging and drug delivery.

Expression of Concern for 'Low-intensity focused ultrasound (LIFU)-activated nanodroplets as a theranostic agent for noninvasive cancer molecular imaging and drug delivery' by Jianxin Liu et al., Biomater. Sci., 2018, 6, 2838-2849, https://doi.org/10.1039/C8BM00726H.

Piezoelectric enhanced sulfur doped graphdiyne nanozymes for synergistic ferroptosis-apoptosis anticancer therapy.

Graphdiyne has excellent potential due to its enzymatic properties. Metal-free sulfur-doped Graphdiyne (S-GDY) has piezoelectric characteristics, and ultrasonic excitation of S-GDY enhances peroxidase activity. It can turn hydrogen peroxide into toxic hydroxyl radicals and induce apoptosis in 4T1 cells. More importantly, the ultrasound (US) enhanced nanozyme induced 4T1 cell ferroptosis by promoting an imbalanced redox reaction due to glutathione depletion and glutathione peroxidase 4 inactivation. S-GDY exhibited enhanced nanozyme activity in vitro and in vivo that may directly trigger apoptosis-ferroptosis for effective tumor therapy. Altogether, this study was expected to provide new insights into the design of piezoelectric catalytic nanozyme and expand their application in the catalytic therapy of tumors.

Development and validation of a transformer-based CAD model for improving the consistency of BI-RADS category 3-5 nodule classification among radiologists: a multiple center study.

Background: Significant differences exist in the classification outcomes for radiologists using ultrasonography-based Breast Imaging Reporting and Data Systems for diagnosing category 3-5 (BI-RADS 3-5) breast nodules, due to a lack of clear and distinguishing image features. Consequently, this retrospective study investigated the improvement of BI-RADS 3-5 classification consistency using a transformer-based computer-aided diagnosis (CAD) model. Methods: Independently, 5 radiologists performed BI-RADS annotations on 21,332 breast ultrasonographic images collected from 3,978 female patients from 20 clinical centers in China. All images were divided into training, validation, testing, and sampling sets. The trained transformer-based CAD model was then used to classify test images, for which sensitivity (SEN), specificity (SPE), accuracy (ACC), area under the curve (AUC), and calibration curve were evaluated. Variations in these metrics among the 5 radiologists were analyzed by referencing BI-RADS classification results for the sampling test set provided by CAD to determine whether classification consistency (the k value), SEN, SPE, and ACC could be improved. Results: After the training set (11,238 images) and validation set (2,996 images) were learned by the CAD model, the classification ACC of the CAD model applied to the test set (7,098 images) was 94.89% in category 3, 96.90% in category 4A, 95.49% in category 4B, 92.28% in category 4C, and 95.45% in category 5 nodules. Based on pathological results, the AUC of the CAD model was 0.924 and the predicted probability of CAD was a little higher than the actual probability in the calibration curve. After referencing BI-RADS classification results, the adjustments were made to 1,583 nodules, of which 905 were classified to a lower category and 678 to a higher category in the sampling test set. As a result, the ACC (72.41-82.65%), SEN (32.73-56.98%), and SPE (82.46-89.26%) of the classification by each radiologist were significantly improved on average, with the consistency (k values) in almost all of them increasing to >0.6. Conclusions: The radiologist's classification consistency was markedly improved with almost all the k values increasing by a value greater than 0.6, and the diagnostic efficiency was also improved by approximately 24% (32.73% to 56.98%) and 7% (82.46% to 89.26%) for SEN and SPE, respectively, of the total classification on average. The transformer-based CAD model can help to improve the radiologist's diagnostic efficacy and consistency with others in the classification of BI-RADS 3-5 nodules.

Bi-DTPA, a potential CT-guided radiation sensitizer.

The therapeutic effects and application of radiotherapy are restricted to some extent due to low radiosensitivity of tumor tissues and adverse effects by excess dosage. Current radiosensitizers are confronted with problems in clinical translation because of complicated manufacture technique and high cost. In this research, we have synthesized a radiosensitizer with advantages in low cost and mass production, which could be applied to CT imaging and enhanced radiotherapy in breast cancer, namely Bi-DTPA. It not only enhanced tumor CT imaging which resulted in better therapeutic accuracy, but also realized radiotherapy sensitization by producing massive ROS and inhibit tumor proliferation, providing a sound perspective in the clinical translation of the radiosensitizer.

A hybrid nanopharmaceutical for specific-amplifying oxidative stress to initiate a cascade of catalytic therapy for pancreatic cancer.

BACKGROUND: Oxidative stress (OS) induced by an imbalance of oxidants and antioxidants is an important aspect in anticancer therapy, however, as an adaptive response, excessive glutathione (GSH) in the tumor microenvironment (TME) acts as an antioxidant against high reactive oxygen species (ROS) levels and prevents OS damage to maintain redox homoeostasis, suppressing the clinical efficacy of OS-induced anticancer therapies. RESULTS: A naturally occurring ROS-activating drug, galangin (GAL), is introduced into a Fenton-like catalyst (SiO2@MnO2) to form a TME stimulus-responsive hybrid nanopharmaceutical (SiO2-GAL@MnO2, denoted SG@M) for enhancing oxidative stress. Once exposed to TME, as MnO2 responds and consumes GSH, the released Mn2+ converts endogenous hydrogen peroxide (H2O2) into hydroxyl radicals (·OH), which together with the subsequent release of GAL from SiO2 increases ROS. The "overwhelming" ROS cause OS-mediated mitochondrial malfunction with a decrease in mitochondrial membrane potential (MMP), which releases cytochrome c from mitochondria, activates the Caspase 9/Caspase 3 apoptotic cascade pathway. Downregulation of JAK2 and STAT3 phosphorylation levels blocks the JAK2/STAT3 cell proliferation pathway, whereas downregulation of Cyclin B1 protein levels arrest the cell cycle in the G2/M phase. During 18 days of in vivo treatment observation, tumor growth inhibition was found to be 62.7%, inhibiting the progression of pancreatic cancer. Additionally, the O2 and Mn2+ released during this cascade catalytic effect improve ultrasound imaging (USI) and magnetic resonance imaging (MRI), respectively. CONCLUSION: This hybrid nanopharmaceutical based on oxidative stress amplification provides a strategy for multifunctional integrated therapy of malignant tumors and image-visualized pharmaceutical delivery.