Long-circulating nanoparticles as passive targeting nanocarriers for the treatment of thrombosis.

Thrombosis is the major cause of cardiovascular diseases. Only a small subset of patients could benefit from thrombolytic therapy due to the high bleeding risk brought about by the repeated administration of thrombolytic drugs. Nanoparticles with targeting ligands have been developed as nanocarriers of thrombolytic drugs to deliver the drug to the thrombus through active targeting. However, the passive targeting effect of nanoparticles on the thrombus is yet to be investigated. Herein, we prepared silica cross-linked micelles (SCLMs) with a long blood circulation half-life as drug carriers to target the thrombus through passive targeting. Compared with SCLMs modified with an active targeting ligand cRGD, the SCLMs exhibited similar targeting behavior to the thrombus in vivo. Loaded with the thrombolytic drug tirofiban, the passive targeting SCLMs showed a comparable therapeutic effect to cRGD-modified SCLMs in a mice model with pulmonary embolism and arterial thrombosis.

Gold nanoclusters-based fluorescence sensor array for herbicides qualitative and quantitative analysis.

Herbicides have been extensively used around the world, which poses a potential hazard to humans and wildlife. Accurate detection of herbicides is crucial for the environment and human health. Herein, a simple and sensitive fluorescence sensor array was constructed for discrimination and identification of herbicides. Fluorescent gold nanoclusters modified with 11-mercaptoundecanoic acid or reduced glutathione were prepared, respectively. Metal ions quenched the fluorescence of nanoclusters through coordination and leading to the aggregation of gold nanoclusters. The addition of auxin herbicides (2,4-dichlorophenoxyacetic acid, 2-methyl-4-chlorophenoxyacetic acid, decamba, picloram, quinclorac) restored the fluorescence of nanoclusters with different degrees. The mechanism study showed auxin herbicides can bind with metal ions and re-disperse the gold nanoclusters from the aggregation state. The "on-off-on" fluorescent sensor array was constructed basic on above detection mechanism. Combined with principal component analysis (PCA) and hierarchical cluster analysis (HCA) methods, auxin herbicides are well separated on 2D/3D PCA score plots and HCA dendrogram in the range of 40-500 µm. In addition, the fluorescence sensor array performed successful in detecting real samples and blind samples. The developed sensor system shows a promising in practical detection of herbicides.

Bromide triggers efficient peroxymonosulfate activation for phosphonate degradation.

Phosphonates have received a widespread attention in wastewater treatment due to their potential threat to the water environment. Advanced oxidation processes (AOPs) are feasible methods to degrade phosphonates, and most of the coexisting substances in water show a negative factor during their oxidation. However, the effect of bromide (Br-) on the degradation of phosphonates in peroxymonosulfate (PMS) activation is still unclear. Herein, using 1-hydroxyethane 1,1-diphosphonic acid (HEDP) as a target phosphonate, Br- could remarkably enhance the degradation of HEDP in PMS activation compared to the PMS alone. Under the condition of pH = 7.0, the optimal degradation efficiency of HEDP is 84.8% in the PMS/Br- process after 30-min reaction, whereas no significant oxidation is obtained in the PMS/I- and PMS/Cl- processes. Multiple experiments (i.e., electron paramagnetic resonance (EPR), radical quenching experiments and chemical probs) confirm that free bromine, SO4•- and HO• paly a minor role in HEDP removal, and bromine radical species make a dominant responsible for HEDP oxidation. Additionally, NO3-, SO42-, Cl-, and HCO3- have a little effect on the degradation of HEDP, but the HEDP removal is greatly inhibited in the presence of humic acid (HA). However, the degradation efficiency of HEDP using PMS/Br- process in river and sewage is a much higher than UV/persulfate (PDS) and UV/H2O2 processes. This study provides a new sight into the effect of Br- on the degradation phosphonates in PMS activation process.

A High-Efficiency Bioorthogonal Tumor-Membrane Reactor for In Situ Selective and Sustained Prodrug Activation.

The site-specific activation of bioorthogonal prodrugs has provided great opportunities for reducing the severe side effects of chemotherapy. However, the precise control of activation location, sustained drug production at the target site, and high bioorthogonal reaction efficiency in vivo remain great challenges. Here, we propose the construction of tumor cell membrane reactors in vivo to solve the above problems. Specifically, tumor-targeted liposomes with efficient membrane fusion capabilities are generated to install the bioorthogonal trigger, the amphiphilic tetrazine derivative, on the surface of tumor cells. These predecorated tumor cells act as many living reactors, transforming the tumor into a "drug factory" that in situ activates an externally delivered bioorthogonal prodrug, for example intratumorally injected transcyclooctene-caged doxorubicin. In contrast to the rapid elimination of cargo that is encapsulated and delivered by liposomes, these reactors permit stable retention of bioorthogonal triggers in tumor for 96 h after a single dose of liposomes via intravenous injection, allowing sustained generation of doxorubicin. Interestingly, an additional supplement of liposomes will compensate for the trigger consumed by the reaction and significantly improve the efficiency of the local reaction. This strategy provides a solution to the efficacy versus safety dilemma of tumor chemotherapy.

Hepatic Stellate Cell-Targeting Micelle Nanomedicine for Early Diagnosis and Treatment of Liver Fibrosis.

Diagnosing and treating liver fibrosis is a challenging yet crucial endeavor due to its complex pathogenesis and risk of deteriorating into cirrhosis, liver failure, and even hepatic cancer. Herein, a silica cross-linked micelles (SCLMs) based nano-system is developed for both diagnosing and treating liver fibrosis. The SCLMs are first modified with peptide CTCE9908 (CT-SCLMs) and can actively target CXCR4, which is overexpressed in activated hepatic stellate cells (HSCs). To enable diagnosis, an ONOO- -responded near-infrared fluorescent probe NOF2 is loaded into the CT-SCLMs. This nano-system can target the aHSCs and diagnose the liver fibrosis particularly in CCl4 -induced liver damage, by monitoring the reactive nitrogen species. Furthermore, a step is taken toward treatment by co-encapsulating two anti-fibrosis drugs, silibinin and sorafenib, within the CT-SCLMs. This combined approach results in a significant alleviation of liver injury. Symptoms associated with liver fibrosis, such as deposition of collagen, expression of hydroxyproline, and raised serological indicators show notable improvement. In summary, the CXCR4-targeted nano-system can serve as a promising theragnostic system of early warning and diagnosis for liver fibrosis, offering hope against progression of this serious liver condition.

Vegetarian diets and the risk of gastrointestinal cancers: a meta-analysis of observational studies.

The systematic review aimed to assess the association between vegetarian diet and the risk of gastrointestinal tumorigenesis. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to August 2022 for observational studies on vegetarian diets and the risk of gastrointestinal tumorigenesis. The primary outcome was morbidity due to gastrointestinal cancer. The Newcastle-Ottawa Scale was used to assess the quality of included studies. Pooled effects were analyzed using a random-effects model. The study protocol was registered in PROSPERO (no. CRD42022310187). Eight original studies (seven cohorts and one case-control), involving 686 691 participants, were included. Meta-analysis showed a negative correlation between vegetarian diets and gastrointestinal tumorigenesis risk [relative risk (RR) equals 0.77, 95% confidence interval (CI) is (0.65-0.90)], compared with non-vegetarian diets. Subgroup analysis indicated that vegetarian diets were negatively correlated with the risks of gastric cancer [RR = 0.41, 95% CI (0.28-0.61)] and colorectal cancer [RR = 0.85, 95% CI (0.76-0.95)], but not with that of upper gastrointestinal cancer (excluding stomach) [RR = 0.93, 95% CI (0.61-1.42)]. Vegetarian diets were negatively correlated with the risk of gastrointestinal tumorigenesis in men [RR = 0.57, 95% CI (0.36-0.91)], but were uncorrelated in women [RR = 0.89, 95% CI (0.71-1.11)]. Vegetarian diets were negatively correlated with the risk of gastrointestinal tumorigenesis in North American [RR = 0.76, 95% CI (0.61-0.95)] and Asian populations [RR = 0.43, 95% CI (0.26-0.72)] and were uncorrelated in the European population [RR = 0.83, 95% CI (0.68-1.01)]. Adhering to vegetarian diets reduces the risk of gastrointestinal tumorigenesis. More data from well-conducted cohort and other studies are needed.

A versatile MOF-derived theranostic for dual-miRNA controlled accurate cancer cell recognition and photodynamic therapy.

Precise detection and monitoring of microRNAs (miRNAs) in living tumor cells is significant for the prompt diagnosis of cancer and provides important information for treatment of cancer. A significant challenge is developing methods for imaging different miRNAs simultaneously to further enhance diagnostic and treatment accuracy. In this work, a versatile MOF-derived theranostic system (DAPM) was constructed using photosensitive metal-organic frameworks (PMOF, PM) and a DNA AND logic gate (DA). The DAPM exhibited excellent biostability and enabled sensitive detection of miR-21 and miR-155, achieving a low limit of detection (LOD) for miR-21 (89.10 pM) and miR-155 (54.02 pM). The DAPM probe generated a fluorescence signal in tumor cells where miR-21 and miR-155 co-existed, demonstrating the enhanced ability of tumor cell recognition. Additionally, the DAPM achieved efficient ROS generation and concentration-dependent cytotoxicity under light irradiation, providing effective photodynamic therapy for anti-tumors. The proposed DAPM theranostic system enables accurate cancer diagnosis, and provides spatial and temporal information for PDT.

Reversal of hepatic fibrosis by the co-delivery of drug and ribonucleoprotein-based genome editor.

Liver fibrosis is a chronic disease without effective treatment in the clinic. Gene editing systems such as the well-known CRISPR/Cas9 have shown great potential in the biomedical field. However, the delivery of the ribonucleoprotein is challenging due to the unstable RNA probe and the requirement for the entrance to the nucleus. Recently, a structure-guided endonuclease (SGN) has been reported as an effective gene-editing system composed of a nuclease and stable DNA probes, which can regulate the protein expression by targeting specific mRNA outside the nucleus. Here, we conjugated the SGN to a nanomicelle as the delivery system. In the resulting material, the chance of the collision between the endonuclease and the probe was raised due to the confinement of the two components within the 40-nm nanomicelle, thus the mRNA can be cleaved immediately after being captured by the probe, resulting in a space-induced nucleotide identification-cleavage acceleration effect. The delivery system was used to treat liver fibrosis via the co-delivery of SGN and a drug rosiglitazone to the hepatic stellate cells, which separately downregulated the expression of tissue inhibitor of metalloprotease-1 and inactivated the hepatic stellate cells. The system successfully reversed the liver fibrosis in mice through the bidirectional regulatory that simultaneously promoted the degradation and inhibited the production of the collagen, demonstrating the great potency of the SGN system as gene medicine.

Silica Cross-Linked Micelle-Based Theranostic System for the Imaging and Treatment of Acute and Chronic Kidney Injury.

Acute kidney injury (AKI) is a common and serious disease with high mortality and morbidity, and the persistent inflammatory environment brought about by AKI promotes its deterioration into chronic kidney disease (CKD). An efficient and timely targeted drug delivery to the renal tubules is crucial for AKI treatment. Here, we prepared silica cross-linked micelles (SCLMs) with different sizes and studied their targeting ability to the injured kidney. It is found that the SCLMs with a size of 13 nm could rapidly accumulate and remain in the damaged kidney. Immunofluorescence results confirmed that SCLMs are selectively located in the damaged tubular cells but cannot be found in healthy renal tissue. Therefore, fluorescent dye-labeled SCLMs were used for the imaging of the injured kidney, which could reflect the status of the kidney injury. Furthermore, atorvastatin, an antioxidative and anti-inflammatory drug, was loaded in SCLMs as the therapeutic agents for the treatment of ischemia/reperfusion-induced AKI and CKD. Renal function indexes, such as tubular necrosis, collagen deposition, and inflammation, were effectively improved after the treatment.

Targeting Warburg effect to rescue the suffocated photodynamic therapy: A cancer-specific solution.

The cancer photodynamic therapy (PDT) is limited by a congenital defect, namely the tumor hypoxia. Cancer cells are characterized by the vigorous oxygen-consuming glycolysis, which is well-known as the "Warburg effect" and one of the primary causes for the hypoxia. Herein, we employed the glucose metabolism as the cancer-specific target to enhance the performance of PDT. The Salvianolic acid B as the inhibitor of glucose uptake and aerobic glycolysis was concomitantly delivered with the photosensitizer chlorin e6 by a redox-responsive organosilica cross-linked micelle. The results demonstrated that the Salvianolic acid B suppressed the glucose metabolism, retarded the oxygen consumption to retain adequate oxygen as the ammo for PDT, which remarkably improve the efficacy of PDT both in vitro and in vivo. Our study not only provides an alternative strategy to address the hypoxia problem for PDT, but also enhances the selectivity of the treatment by targeting the cancer-specific Warburg effect.

Activation of Brain Regions Associated with Working Memory and Inhibitory Control in Patients with Attention-Deficit/Hyperactivity Disorder in Functional Near-Infrared Spectroscopy: A Systematic Review.

INTRODUCTION: Patients with attention-deficit/hyperactivity disorder (ADHD) often show abnormalities related to cognitive activities, especially related to working memory and inhibitory control. Functional near-infrared spectroscopy (fNIRS) is a non-invasive brain imaging technique based on the changes in cerebral hemodynamics to measure the response of brain activities to cognitive tasks. METHODS: In this review, we collected all clinical experiments that evaluated the changes of oxyhemoglobin levels in relevant brain regions of patients with ADHD through cognitive tasks by fNIRS to determine the abnormalities of brain regions related to working memory and inhibitory control activities in patients with ADHD. RESULTS: From the beginning of November 2021, PubMed, PsycINFO, Scopus, EMBASE, CINAHL, web of science and Cochrane library were searched, and ROBINS-I was a tool to evaluate the quality and risk bias of the articles included. Sixteen eligible clinical trials or randomized controlled trials were included, of which six measured working memory and eleven measured inhibitory control. CONCLUSION: We found that compared with healthy people, the activation scope of working memory and inhibition control in the frontal cortex in ADHD patients was smaller than that in healthy people, and the activation degree was weak or even inactive, which can provide new ideas for the direction of research on ADHD.

Real-Time Visualization of the Antioxidative Potency of Drugs for the Prevention of Myocardium Ischemia-Reperfusion Injury by a NIR Fluorescent Nanoprobe.

The burst of the reactive oxygen species (ROS) is the culprit of myocardial ischemia-reperfusion injury. As direct ROS scavengers, antioxidants are clinically documented drugs for the prevention of reperfusion injury. However, some drugs give disappointing therapeutic performance despite their good in vitro effects. Therefore, in vivo assessments are necessary to screen the antioxidants before clinical trials. However, traditional methods such as histological study require invasive and complicated preprocessing of the biological samples, which may fail to reflect the actual level of the unstable ROS with a very short lifetime. Peroxynitrite (ONOO-) is a characteristic endogenous ROS produced during reperfusion. Here, we modified the ONOO--responsive near-infrared fluorescent probe on a myocardium-targeting silica cross-linked micelle to prepare a nanoprobe for the real-time monitoring of ONOO- during coronary reperfusion. A ROS-stable cyanine dye was co-labeled as an internal reference to achieve ratiometric sensing. The nanoprobe can passively target the infarcted myocardium and monitor the generation of ONOO- during reperfusion in real-time. The antioxidants, carvedilol, atorvastatin, and resveratrol, were used as model drugs to demonstrate the capability of the nanoprobe to evaluate the antioxidative potency in situ. The drugs were either loaded and delivered by the nanoprobe to compare their in vivo efficacy under similar concentrations or administered intraperitoneally as a free drug to take their pharmacokinetics into account. The imaging results revealed that pharmacokinetics might be the determinant factor that influences the efficacy of the antioxidants.

An ultrasensitive lipid droplet-targeted NIR emission fluorescent probe for polarity detection and its application in liver disease diagnosis.

Compared to normal cells, cancer cells require more energy supply during proliferation and metabolism. In living cells, in addition to mitochondria, lipid droplets are also an important organelle for providing energy. Studies have shown that the number and distribution of lipid droplets change significantly during the production of lesions in cells. At this stage, the predisposing factors for the development of cellular lesions are not clear, thus leading to limitations in the early diagnosis and treatment of diseases such as liver injury, fatty liver, and hepatitis. To meet the urgent challenge, we used a near-infrared emission fluorescent probe SSR-LDs based on the intramolecular charge transfer effect (ICT) to detect polarity changes within intracellular lipid droplets. The probe SSR-LDs has ultra-sensitive polarity sensitivity, excellent chemical stability and photo-stability. In addition, by comparing normal and cancer cells through cell imaging experiments, we found that the robust probe has the ability to sensitively monitor the changes in lipid droplet polarity in the living cells. More importantly, using the constructed fluorescent probe, we have achieved an in vitro fluorescence detection of liver injury and fatty liver, and the detection of hepatitis at the in vivo level. The unique fluorescent probe SSR-LDs is expected to serve as a powerful tool for the medical diagnosis of diseases related to lipid droplet polarity.

Myocardium-Targeted Micelle Nanomedicine That Salvages the Heart from Ischemia/Reperfusion Injury.

Cardioprotective medication is the common treatment to relieve myocardial ischemia/reperfusion (I/R) injury. However, limited by the low bioavailability of therapeutic drugs, the therapeutic outcome is barely satisfactory. Because the I/R injury can enhance the permeability of the vasculature and allow the extravasation of nanoparticles into the surrounding tissue, herein we formulate the cardiotonic drug olprinone (Olp) in cross-linked micelles as the nanomedicine to achieve myocardium-targeted delivery after systematic administration. As a result, the local concentration of Olp in the injured myocardium is raised by orders of magnitude with prolonged drug duration time. The treatment successfully preserves the pumping efficiency of the heart, alleviates ventricular remodeling, and thus stops the positive feedback loop for the deteriorated cardiac function. Consequently, the myocardium-targeted nanomedicine significantly salvages the heart from I/R injury before irreversible pathological changes take place.

A new NIR emission mitochondrial targetable fluorescent probe and its application in detecting viscosity changes in mouse liver and kidney injury.

As important organs of the human body, the liver and kidneys ensure the stability of the internal environment of the body and allow the body to carry out normal metabolism. The lack of effective methods for early diagnosis of liver and kidneys diseases is an important reason for delaying the treatment of kidney diseases. Therefore, the development of a simple, non-invasive and effective test is essential for the early diagnosis of liver and kidneys disease. Herein, a new viscosity fluorescent probe, Mito-ND, is rationally designed and synthesized in order to solve the practical problem of realizing the diagnosis of liver and kidneys diseases. The constructed fluorescent probe Mito-ND has the advantages of near-infrared emission, mitochondrial localization, high chemical and photo-stable properties, and sensitive viscosity detection performance, etc. Using this fluorescent probe, besides in vitro cell viscosity fluorescence imaging, the viscosity fluorescence imaging of mouse liver and kidney injury are also achieved for the first time. Mito-ND provides more accurate tools for the non-invasive diagnosis of viscosity-related diseases such as liver injury and kidney injury. Therefore, Mito-ND provides more accurate detection techniques for the early diagnosis of liver and kidney diseases such as liver injury and kidney injury.

Biomarker-Responsive Fluorescent Probes for In-Vivo Imaging of Liver Injury.

Liver injury-related diseases have aroused widespread concern due to their extreme unpredictability, acute onset, and severe consequences. Nowadays, the clinical prediction and assessment of liver injury mainly focus on histopathological and serological approaches, which require a tedious process and sometimes invasive biopsy. Over the past decades, fluorescence imaging techniques have emerged for the diagnosis of diseases owing to their noninvasiveness, high fidelity and ease of operation. With regard to liver injury, fluorescent probes have been delicately designed to respond to a variety of endogenous biomolecules to precisely offer comprehensive information about the lesion site. Herein, we make a brief summary and discussion about the design strategies and applications of recently reported fluorescent biosensors responsive to a series of biomarkers involved in liver injury. The potential prospects and remaining challenges are also discussed to promote the progression in this field.

Sensing and imaging of PPi in vivo using lanthanide-based second near-infrared luminescent probes.

Inorganic pyrophosphate (PPi), as a biologically active anion, is closely related to physiological activities and several pathological changes. Here, we reported a luminescent nanoprobe for the detection and imaging of PPi in vivo based on lanthanide nanoparticles with luminescence at the second near-infrared window modified by the tannic acid and Fe3+ complex. A light-harvesting complex was formed after the coordination of colorless tannic acid with Fe3+ and the luminescence of the nanoparticles was quenched through the inner-filter effect. In the presence of PPi, the complex was decomposed due to the stronger coordination affinity of PPi to Fe3+; thus the luminescence of the nanoprobe was recovered. The nanoprobe manifested good linearity with a low detection limit of 3.36 µM. Importantly, in the in vivo study simulating the calcium pyrophosphate deposition disease, the nanoprobe with the second near-infrared luminescence achieved the imaging of the injected PPi at the paw of the mice at a dose of 0.25 mg kg-1. The reported nanoprobe can serve as a convenient tool for the in vivo imaging of PPi and the diagnosis of PPi-related diseases.

A simple paper-based ratiometric luminescent sensor for tetracyclines using copper nanocluster-europium hybrid nanoprobes.

Tetracyclines (TCs), as one of the broad-spectrum antibiotics, are widely used to treat bacterial infections. The residues of TCs in animal-origin foods and drinking water have raised safety concerns and affected the public health. Thus, there is a high demand to develop a simple and rapid method for the detection of TCs. In this work, we developed a ratiometric luminescence probe for the sensitive and visualized detection of TCs. Specifically, tannic acid-stabilized copper nanoclusters (TA-CuNCs) with blue emission at 433 nm were synthesized. The luminescence of TA-CuNCs attenuated partially by the europium ions (Eu3+) due to the aggregation-induced quenching. When TCs were added to the TA-CuNCs-Eu3+ system, the luminescence of TA-CuNCs at 433 nm can be further quenched by the inner-filter effect, and the characteristic luminescence of Eu3+ at 617 nm emerged due to the formation of Eu3+-TCs complex. The ratio of the luminescence at 617 nm-433 nm increased linearly to the concentration of TCs. Additionally, we demonstrated the detection of oxytetracycline in real samples such as tap and lake water, milk, pharmaceutical industry wastewater, honey and soil extract with high recovery rate (97.25%-103.44%). Furthermore, a portable paper device is fabricated by the luminescent probe to conduct the on-site analysis of TCs.

The screening of drug-induced nephrotoxicity using gold nanocluster-based ratiometric fluorescent probes.

Herbal medicines are potential candidates for the treatment of various diseases, but their medication safety remains poorly regulated. Current screening methods for the herbal medicine-induced nephrotoxic effects include histological and serological assessments, which often fail to reflect the kidney dysfunction instantly. Here we report a ratiometric fluorescence approach for the rapid and facile screening of drug-induced acute kidney injury using chromophore-modified gold nanoclusters. These gold nanoclusters are highly sensitive to reactive oxygen species (ROS), with a detection limit of 14 nM for ˙OH. After passing through the glomerular filtration barrier, the gold nanocluster-based probes can quantify the fluctuation of the ROS level in the kidneys and evaluate the risk of drug-induced nephrotoxicity. We further employed nephrotoxic triptolide as the model drug and the screening of drug-induced early renal injury was demonstrated using the nanoprobes, which is unattainable by conventional diagnostic approaches. Our fluorescent probes also allow the identification of other nephrotoxic components from herbal medicine such as aristolochine, providing a high-throughput strategy for the screening of herbal supplement-induced nephrotoxicity.

Real-Time Imaging of Hepatic Inflammation Using Hydrogen Sulfide-Activatable Second Near-Infrared Luminescent Nanoprobes.

The sensing and visualized monitoring of hydrogen sulfide (H2S) in vivo is crucial to understand its physiological and pathological roles in human health and diseases. Common methods for H2S detection require the destruction of the biosamples and are not suitable to be applied in vivo. In this Communication, we report a "turn-on" second near-infrared (NIR-II) luminescent approach for sensitive, real-time, and in situ H2S detection, which is based on the absorption competition between the H2S-responsive chromophores (compound 1) and the NIR-II luminescent lanthanide nanoparticles. Specifically, the luminescence was suppressed by compound 1 due to the competitive absorption of the incident light. In the presence of H2S, the compound 1 was bleached to recover the luminescence. Thanks to the deep tissue penetration depth and the low absorbance/scattering on biological samples of the NIR-II nanoprobes, the monitoring of the endogenous H2S in lipopolysaccharide-induced liver inflammation was achieved, which is unattainable by the conventional histopathological and serological approaches.