Search

Gold nanoparticles (AuNPs) are extensively utilized in biomolecular sensing, photothermal therapy, drug delivery, and various imaging techniques like photoacoustic and fluorescent imaging. Despite their diverse applications, inconsistent findings from previous toxicity studies underscore the critical need for standardized methodologies. This study introduces ten distinct types of AuNPs─cubes, stars, rods, dumbbells, and bipyramids at sizes of 50 and 100 nm, to systematically assess their toxicity under controlled conditions both in vitroand in vivo. Our findings reveal a clear correlation between cytotoxicity and the morphology, size, incubation duration, and concentration of AuNPs. Anisotropically shaped nanoparticles, such as nanorods, nanodumbbells, and nanobipyramids, tend to exhibit higher cytotoxicity compared to more spherical forms like nanocubes and nanostars. Interestingly, while in vivoplasma biochemistry parameters show minimal variation, biodistribution, histopathological alterations, and pharmacokinetics are notably influenced by the shape and size of AuNPs. In most instances, smaller and anisotropic AuNPs that remain in the bloodstream for extended periods are observed. This research offers significant insights into the design of AuNPs with specific morphologies and sizes, particularly for their application in drug delivery systems viaintravenous injection. These outcomes emphasize the nuanced toxicity profiles of AuNPs, necessitating tailored approaches in preclinical and clinical research.

Urinary tract infection (UTI) is a common and prevalent disease caused by a spectrum of pathogens. Lack of access to rapid, portable, and high-quality diagnostics in resource-limited settings aggravates the improper treatment of UTIs, which is also a major driver of antibiotic misuse worldwide. Here, we describe a custom-made portable colorimetric array (PoCA) for reading out polymerase chain reaction (PCR) amplicons, the rationale of which is to transfer the previously developed dsDNA-based photosensitization colorimetric assay (solution) onto paper discs for detection. By integrating mini-LED irradiation and paper discs, the PoCA can read out 96 PCR tests in one pot, thus allowing diagnosis and identification of 12 prevailing UTI pathogens in less than 2 h, coupled with a portable thermal cycler for PCR. After analyzing 200 clinical urine samples, the pathogen profiling accuracy of the PoCA was demonstrated to be higher than the standard urine culture (confirmed with metagenomic next-generation sequencing). The PoCA platform could be used in primary care for rapid UTI diagnosis and pathogen identification.

Targeting Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages using RNAi nanotechnology represents an innovative and promising strategy in the diagnosis and treatment of atherosclerosis. Nevertheless, it remains elusive because of the current challenges associated with the systemic delivery of siRNA nanoparticle (NP) to atheromatous plaques and the complexity of atherosclerotic plaques. Here, we demonstrate the potential of a thienothiadiazole-based near-infrared-II (NIR-II) organic aggregation-induced emission (AIE) platform encapsulated with the Camk2g siRNA to effectively target CaMKIIγ in macrophages for dynamic imaging and image-guided gene therapy of atherosclerosis. The nanoparticles effectively decreased CaMKIIγ expression and increased the expression of the efferocytosis receptor MerTK in plaque macrophages, leading to a reduction in the necrotic core area of the lesion in an aortic plaque model. Our theranostic approach highlights the substantial promise of near-infrared II (NIR-II) AIEgens for imaging and image-guided therapy of atherosclerosis.

Fluorescence and photoacoustic (PA) imaging in the second near-infrared (NIR-II, 1000–1700 nm) window has garnered massive interest owing to high maximum permissible exposure of light, reduced autofluorescence, and improved deep penetration. However, active targeted NIR-II photoacoustic/NIR-IIa fluorescence imaging of glioma under NIR-II excitation has been seldom reported, which is partly ascribable to the lack of suitable materials. In this study, a small-molecule-based αvβ3-targeted NIR-II photoacoustic/NIR-IIa fluorescent probe IR-32pwas generated and subsequently evaluated in U87MG tumor-bearing mice excited with NIR-I and NIR-II light. Exceptional dual-modal imaging properties such as good tumor uptake, high targeting specificity, and high tumor contrast were achieved in an orthotopic glioma model under 1020/1064 nm excitation, exhibiting a superior imaging depth of glioma through the skull. Our study introduces an outstanding dual-modal contrast agent with NIR-II absorption and confirms the superiority of NIR-II excitation over NIR-I in in vivo NIR-II/PA imaging.

Messenger RNA (mRNA) therapy has shown tremendous potential for different diseases including cancer. While mRNA has been extensively used in cancer vaccine development as antigen or in cancer immunotherapy as immunomodulatory agent, the combination of mRNA therapy with photodynamic therapy has not been explored in cancer treatment. Herein, we report a reactive oxygen species (ROS)-responsive polymeric nanoparticle (NP) platform for first-in-field codelivery of mRNA and photosensitizer for effective cancer treatment. We developed ROS-responsive oligomer-based polymeric NPs and applied them to test a combination of p53 mRNA and indocyanine green (ICG). The ROS-triggered disassembly of the NPs could promote mRNA translation efficiency, whereby p53 expression induced apoptosis of lung tumor cells. Meanwhile, the released ICG could lead to generation of ROS under 808 nm laser irradiation to induce photodynamic therapy. The NP codelivery of p53 mRNA and ICG demonstrated an effective and safe anti-tumor effect in a lung cancer model.

The clinical success of cisplatin ushered in a new era of the application of metallodrugs. When it comes to practice, however, drug resistance, tumor recurrence, and drug systemic toxicity make it implausible to completely heal the patients. Herein, we successfully transform an electron acceptor [1, 2, 5]thiadiazolo[3,4-g]quinoxaline into a novel second near-infrared (NIR-II) fluorophore H7. After PEGylation and chelation, HL-PEG2kexhibits a wavelength bathochromic shift, enhanced photothermal conversion efficiency (41.77%), and an antineoplastic effect against glioma. Its potential for in vivo tumor tracking and image-guided chemo-photothermal therapy is explored. High levels of uptake and high-resolution NIR-II imaging results are thereafter obtained. The hyperthermia effect could disrupt the lysosomal membranes, which in turn aggravate the mitochondria dysfunction, arrest the cell cycle in the G2 phase, and finally lead to cancer cell apoptosis. HL-PEG2kdisplays a superior biocompatibility and thus can be a potential theranostic platform to combat the growth and recurrence of tumors.

Klebsiella aerogenesis an understudied and clinically important pathogen. We therefore investigate its population structure by genome analysis aligned with metadata. We sequence 130 non-duplicated K. aerogenesclinical isolates and identify two inter-patient transmission events. We then retrieve all publicly available K. aerogenesgenomes (n = 1,026, accessed by January 1, 2023) and analyze them with our 130 genomes. We develop a core-genome multi-locus sequence-typing scheme. We find that K. aerogenesis a species complex comprising four phylogroups undergoing evolutionary divergence, likely forming three species. We delineate remarkable clonal diversity and identify three worldwide-distributed carbapenemase-encoding clonal clusters, representing high-risk lineages. We uncover that K. aerogeneshas an open genome equipped by a large arsenal of antimicrobial resistance genes. We identify two genetic regions specific for K. aerogenes, encoding a type VI secretion system and flagella/chemotaxis for motility, respectively, both contributing to the virulence. These results provide much-needed insights into the population structure and pan-genomes of K. aerogenes.

Fluorescence imaging in the second near-infrared window(NIR-II, 1000―1700 nm) has demonstrated tremendous promise for biomedical applications, with its extraordinarily high resolution and deep tissue penetration. Ultrasmall gold nanoclusters(AuNCs) have shown unique features for NIR-II imaging, such as photostability and biocompatibility, as compared to organic NIR-II molecules or other inorganic NIR-II nanoparticles. Here, we report the first-in-class protein-capped ultrasmall AuNCs(BSA-AuNCs, BSA=bovine serum albumin) for simultaneous NIR-II imaging and photodynamic therapy. The BSA-AuNCs show a uniform size, high quantum yield and excellent photostability, display a high accumulation and long retention in 4T1 tumor, and are used for clear imaging of blood vessels and lymph nodes. Moreover, laser irradiation of these AuNCs can rapidly trigger ROS generation, leading to effective inhibition of tumor cell growth in vitroand in vivo. This study demonstrates the feasibility of a protein-capped ultrasmall AuNCs platform for theranostic applications by combining NIR-II imaging and photodynamic cancer therapy.

Small-molecule fluorescence imaging in the second near-infrared (NIR-II, 1000–1700 nm) window has gained increasing interest in clinical application. Till now, very few studies have been exploited in the small-molecule fluorophores with both excitation and emission in the NIR-II window. Inspired by the indocyanine green structure, a series of polymethine dyes with both absorption and emission in the NIR-II window have been developed for NIR-II imaging, providing the feasibility to directly compare optical imaging in the NIR-IIa (1300–1400 nm) subwindow under 1064 nm excitation with that in the NIR-II window under 808 nm excitation. The signal–background ratio and the tumor–normal tissue ratio achieved great improvement under 1064 nm excitation in the imaging of mouse blood pool and U87 glioma tumors. Our study not only introduces a broadband emission fluorophore for both NIR-II and NIR-IIa imaging, but also reveals the advantages of NIR-II excitation over NIR-I in in vivo imaging.

Articular cartilage (AC) is a complex water-bearing tissue consisting of chondrocytes, proteoglycans, and collagen. AC degeneration, which occurs in the early stage and throughout the entire course of osteoarthritis (OA), is one of the main pathological changes of OA. However, current clinical approaches are unable to detect AC degradation during the early stage of OA. Herein, a novel NIR-II probe, CH1055-WL, was developed with an organic fluorophore (CH1055) and type II collagen-binding peptide (WYRGRL) for AC targeting and degeneration imaging. In vitroand in vivoimaging studies demonstrated that CH1055-WLspecifically bound to AC and permitted sensitive detection of age-related or surgically induced AC degeneration in living mice. In vitroimaging of cartilage samples from pig knee joint and in vivoimaging of live mice with the probe administered vialocal injection in joint cavities demonstrated that CH1055-WLspecifically and efficiently bound to AC. Further evaluation of CH1055-WLrevealed sensitive detection of age-related AC degeneration and surgically induced AC degeneration in living mice. Our results indicated that the cartilage-targeting probe CH1055-WLallowed visual monitoring of AC degeneration in living subjects, thus displaying promise for early OA detection.

Compared to the well-studied NIR-I small-molecule fluorophores, the structures of NIR-II fluorophores are scarce yet. Most NIR-II fluorophores are composed of D-A-D structures. It is essential to search for the new structures of NIR-II fluorophores to enlarge the field of NIR-II dyes.

Targeted therapy of hepatocellular carcinoma (HCC) is essential for improved therapies. Therefore, identification of key targets specifically to HCC is an urgent requirement. Herein, an iTRAQ quantitative proteomic approach was employed to identify differentially expressed proteins in HCC tumor tissues. Of the upregulated tumor-related proteins, minichromosome maintenance 2 (MCM2), a DNA replication licensing factor, was one of the most significantly altered proteins, and its overexpression was confirmed using tissue microarray. Clinicopathological analysis of multiple cohorts of HCC patients indicated that overexpression of MCM2 was validated in 89.8% tumor tissues and strongly correlated with clinical stage. Furthermore, siRNA-mediated repression of MCM2 expression resulted in significant suppression of the HepG2 cell cycle and proliferation through the cyclin D-dependent kinases (CDKs) 2/7 pathway. Finally, the first small molecule-based MCM2-targeted NIR-II probe CH1055-MCM2was concisely generated and subsequently evaluated in mice bearing HepG2 xenografts. The excellent imaging properties such as good tumor uptake and high tumor contrast and specificity were achieved in the small animal models. This analytical strategy can determine novel accessible targets of HCC useful for imaging and therapy.

ABSTRACTOur case series showed that uncomplicated Yarrowia lipolyticafungemia might be treated with catheter removal alone. The Vitek 2 YST identification (ID) card system, matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), and internal transcribed spacer and 25S nuclear ribosomal DNA (nrDNA) gene sequencing provided reliable identification. All isolates had low MICs to voriconazole, echinocandins, and amphotericin B.

Resolving atheroma and hindering their transition to vulnerable atherosclerotic plaque is pivotal in preventing deadly episodes such as heart attacks and strokes. Despite recent advances in the treatment, atherosclerosis remains the root cause of death worldwide. Excess cholesterol accumulation and deposition trigger a complex inflammatory response in atherosclerosis. Our recent studies demonstrate that epsins, a family of endocytic adaptors, are critically responsible for the aforesaid events in atherosclerosis; however, the underlying mechanisms and whether targeting epsins hinders cholesterol uptake, promote cholesterol efflux and reverse transport in macrophages to reduce inflammation and accelerate atheroma resolution remains an open question. To explore the therapeutic intervention by harnessing recent development in nanomedicine, we silenced epsins in lesional macrophages by specific delivery of nanoparticles (NPs) carrying epsin siRNAs. We showed that inhibit epsins significantly diminished atherosclerotic plaque size and promoted plaque regression. Mechanistically, epsins bind to CD36 to facilitate CD36-mediated lipid uptake by enhancing its endocytosis and recycling. Conversely, epsins promote ABCG1 degradation via lysosomes and hamper ABCG1-mediated cholesterol efflux and reverse cholesterol transport. Furthermore, myeloid-specific epsins double knockout mice (LysM-DKO) harboring a genetically reduced ABCG1 level (LysM-DKO-ABCG1fl/+) were generated. In LysM-DKO-ABCG1fl/+macrophages, enhanced cholesterol efflux and reverse transport due to epsins deficiency was suppressed. Our findings suggest that targeting epsins in lesional macrophages may offer therapeutic benefits in preventing or treating advanced atherosclerosis.

A facile synthetic approach to 3'-substituted-5-cyclopropanespirohydantoins has been developed and used to synthesize some new spirohydantoins. The key aspect is the preparation of α-carboethoxy isocyanate basing on Curtius rearrangement, which can be ring-closed to the expected spirohydantoins after the reaction with various amines and hydrazines. Interestingly the cyclopropane ring doesn't open during the whole process.

Complete excision of the last remaining 1–2% of tumor tissue without collateral damage remains particularly challenging. Herein, we report thiophenthiadiazole (TTD)-derived fluorophores L6-PEGnk(n= 1, 2, 5) as new-generation NIR-II (1000–1700 nm) probes with exceptional nonfouling performance and significantly high fluorescence quantum yields in water. L6-PEG2kcan self-assemble into vesicular micelles and exhibited minimal immunogenicity, low binding affinities, ultralong blood circulation (t1/2= 59.5 h), and a supercontrast ratio in vivo. Most importantly, L6-PEG2kachieved excellent in vivoCT-26 and U87MG tumor targeting and accumulation (>20 d) through intraperitoneal or intravenous injection. A subcutaneous U87MG tumor and orthotopic brain glioma were successfully resected under NIR-II FIGS in our animal model via intraperitoneal injection in an extended time window (48–144 h). This study highlights the potential of using L6-PEG2Kas self-assembling molecular probes with long-circulation persistence for routine preoperative tumor assessment and precise intraoperative image-guided resection.

Osteosarcoma is an aggressive tumor of mesenchymal origin that is more likely to spread to the lung than others, with a major impact on patients' prognosis. The optimal imaging method that can reliably detect or exclude pulmonary metastases from osteosarcoma is still scarce. Herein, two homologous types of fluorescent probes CH1055‐PEG‐PTand CH1055‐PEG‐Affibody, which show highly promising results for targeting imaging of osteosarcoma and its lung metastasis, respectively, are designed and synthesized. It is found that the NIR‐II imaging quality of CH1055‐PEG‐PTis far superior to that of computed tomography for the early in vivo 143B tumor imaging, and this probe‐guided surgery for accurate resection of 143B tumor is further performed. The high‐resolution visualization of primary and micrometastatic lung lesions of osteosarcoma by using CH1055‐PEG‐Affibodyis also demonstrated. Therefore, the attractive imaging properties of CH1055‐PEG‐PTand CH1055‐PEG‐Affibody, including high levels of uptakes, and high spatial and temporal resolution, open up opportunities for molecular imaging and clinical translation of osteosarcoma and its lung metastasis in the unique second near‐infrared window. Two homologous types of small‐molecule NIR‐II probes CH1055‐PEG‐PTand CH1055‐PEG‐Affibodyare designed and synthesized to detect primary osteosarcoma, while CH1055‐PEG‐Affibodycan even visualize lung metastasis by NIR‐II imaging.

Redox-sensitive mRNA nanoparticles help kill tumors by restoring p53 expression.

The development of novel biodegradable and nontoxic fluorophores that integrate diagnosis and therapy for effective cancer treatment has obtained tremendous attention in the past decades. In this report, water‐soluble and biocompatible small‐molecule near‐infrared II (NIR‐II) fluorescent dye H2a‐4T complexed with fetal bovine serum (FBS) and Cetuximab proteins with excellent optical properties and targeting ability is prepared. High spatial and temporal resolution imaging of hind limb vasculature and the lymphatic system of living mice using H2a‐4T@FBS complex is demonstrated in precise NIR‐II imaging‐guided sentinel lymph node surgery. More importantly, H2a‐4T@Cetuximab complex not only exhibits a remarkable cell‐killing ability but also achieves highly active tumor targeting efficiency for epidermal growth factor receptor, overexpressing colorectal cancer which is beneficial to in vivo NIR‐II fluorescent imaging‐guided photothermal therapy of colon tumors. To the best of our knowledge, it is the first time that the concept of light‐harvesting complex is exploited for enhancing the NIR‐II signals and photothermal energy conversion in molecule‐protein complex theranostic agent, making them a promising candidate for future clinical applications in cancer theranostics. The first light‐harvesting complexproduced by noncovalent interaction between a small‐molecule organic NIR‐II fluorophore and proteins is facilely assembled and used for not only NIR‐II fluorescent imaging of hind limb vasculature and lymphatic system, but also NIR‐II imaging‐guided lymph node surgery and photothermal therapy.

Twenty new title derivatives are synthesized via conversion of monoester (I) to the corresponding acyl azide, Curtius reaction, followed by reaction of the formed isocyanate with arylacethydrazides (II) to afford the semicarbazides (III), which cyclize upon treatment with a base to provide the spirohydantoins (IV) as racemic mixtures.